195 results on '"Barbara Rehermann"'
Search Results
2. Serum neutralization activity declines but memory B cells persist after cure of chronic hepatitis C
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Akira Nishio, Sharika Hasan, Heiyoung Park, Nana Park, Jordan H. Salas, Eduardo Salinas, Lela Kardava, Paul Juneau, Nicole Frumento, Guido Massaccesi, Susan Moir, Justin R. Bailey, Arash Grakoui, Marc G. Ghany, and Barbara Rehermann
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Science - Abstract
Long-term dynamics of the humoral response to HCV in cured individuals aren’t well understood. Here, Nishio et al. show that virus-neutralizing antibody levels decrease in potency and breadth after cure of chronic hepatitis C, while HCV-specific memory B cells persist.
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- 2022
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3. Discovery of several thousand highly diverse circular DNA viruses
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Michael J Tisza, Diana V Pastrana, Nicole L Welch, Brittany Stewart, Alberto Peretti, Gabriel J Starrett, Yuk-Ying S Pang, Siddharth R Krishnamurthy, Patricia A Pesavento, David H McDermott, Philip M Murphy, Jessica L Whited, Bess Miller, Jason Brenchley, Stephan P Rosshart, Barbara Rehermann, John Doorbar, Blake A Ta'ala, Olga Pletnikova, Juan C Troncoso, Susan M Resnick, Ben Bolduc, Matthew B Sullivan, Arvind Varsani, Anca M Segall, and Christopher B Buck
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viral evolution ,metagenomics ,microbiome ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
Although millions of distinct virus species likely exist, only approximately 9000 are catalogued in GenBank's RefSeq database. We selectively enriched for the genomes of circular DNA viruses in over 70 animal samples, ranging from nematodes to human tissue specimens. A bioinformatics pipeline, Cenote-Taker, was developed to automatically annotate over 2500 complete genomes in a GenBank-compliant format. The new genomes belong to dozens of established and emerging viral families. Some appear to be the result of previously undescribed recombination events between ssDNA and ssRNA viruses. In addition, hundreds of circular DNA elements that do not encode any discernable similarities to previously characterized sequences were identified. To characterize these ‘dark matter’ sequences, we used an artificial neural network to identify candidate viral capsid proteins, several of which formed virus-like particles when expressed in culture. These data further the understanding of viral sequence diversity and allow for high throughput documentation of the virosphere.
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- 2020
- Full Text
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4. Natural Killer Cells in Viral HepatitisSummary
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Barbara Rehermann
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Diseases of the digestive system. Gastroenterology ,RC799-869 - Abstract
Natural killer (NK) cells are traditionally regarded as first-line effectors of the innate immune response, but they also have a distinct role in chronic infection. Here, we review the role of NK cells against hepatitis C virus (HCV) and hepatitis B virus (HBV), two agents that cause acute and chronic hepatitis in humans. Interest in NK cells was initially sparked by genetic studies that demonstrated an association between NK cellârelated genes and the outcome of HCV infection. Viral hepatitis also provides a model to study the NK cell response to both endogenous and exogenous type I interferon (IFN). Levels of IFN-stimulated genes increase in both acute and chronic HCV infection and pegylated IFNα has been the mainstay of HCV and HBV treatment for decades. In chronic viral hepatitis, NK cells display decreased production of antiviral cytokines. This phenotype is found in both HCV and HBV infection but is induced by different mechanisms. Potent antivirals now provide the opportunity to study the reversibility of the suppressed cytokine production of NK cells in comparison with the antigen-induced defect in IFNγ and tumor necrosis factor-α production of virus-specific T cells. This has implications for immune reconstitution in other conditions of chronic inflammation and immune exhaustion, such as human immunodeficiency virus infection and cancer. Keywords: HBV, HCV, Infection, Interferon, T Cell
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- 2015
- Full Text
- View/download PDF
5. Natural versus Laboratory World: Incorporating Wild-Derived Microbiota into Preclinical Rodent Models
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Barbara Rehermann and Ji Hoon Oh
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Host Microbial Interactions ,Rodent ,Gene Expression Profiling ,Immunology ,Laboratory mouse ,Animals, Wild ,Translational research ,Computational biology ,Human physiology ,Biology ,Infections ,Commensalism ,Genome ,Disease Models, Animal ,Mice ,Metabolomics ,Animals, Laboratory ,biology.animal ,Animals ,Germ-Free Life ,Humans ,Immunology and Allergy ,Metagenomics ,Microbiome - Abstract
Advances in data collection (high-throughput shotgun metagenomics, transcriptomics, and metabolomics) and analysis (bioinformatics and multiomics) led to the realization that all mammals are metaorganisms, shaped not only by their own genome but also by the genomes of the microbes that colonize them. To date, most studies have focused on the bacterial microbiome, whereas curated databases for viruses, fungi, and protozoa are still evolving. Studies on the interdependency of microbial kingdoms and their combined effects on host physiology are just starting. Although it is clear that past and present exposure to commensals and pathogens profoundly affect human physiology, such exposure is lacking in standard preclinical models such as laboratory mice. Laboratory mouse colonies are repeatedly rederived in germ-free status and subjected to restrictive, pathogen-free housing conditions. This review summarizes efforts to bring the wild microbiome into the laboratory setting to improve preclinical models and their translational research value.
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- 2021
6. Insights From Antiviral Therapy Into Immune Responses to Hepatitis B and C Virus Infection
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Robert Thimme and Barbara Rehermann
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0301 basic medicine ,Hepatitis B virus ,HBsAg ,Hepatology ,business.industry ,Hepatitis C virus ,Gastroenterology ,virus diseases ,Hepatitis B ,medicine.disease_cause ,medicine.disease ,digestive system diseases ,Virus ,03 medical and health sciences ,Liver disease ,030104 developmental biology ,0302 clinical medicine ,Immune system ,Immunity ,Immunology ,Medicine ,030211 gastroenterology & hepatology ,business - Abstract
There are 257 million persons worldwide with chronic hepatitis B virus (HBV) infection, a leading causes of liver cancer. Almost all adults with acute HBV infection have a rapid immune response to the virus, resulting in life-long immunity, but there is no cure for individuals with chronic HBV infection, which they acquire during early life. The mechanisms that drive the progression of HBV through distinct clinical phases to end-stage liver disease are poorly understood. Likewise, it is not clear whether and how immune responses can be modulated to allow control and/or clearance of intrahepatic HBV DNA. We review the innate and adaptive immune responses to acute and chronic HBV infections and responses to antiviral therapy. Comparisons with hepatitis C virus infection provide insights into the reversibility of innate inflammatory responses and the potential for successful therapy to recover virus-specific memory immune responses.
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- 2019
7. Neonatal exposure to a wild-derived microbiome protects mice against diet-induced obesity
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Stephan P. Rosshart, Oksana Gavrilova, Jonathan H. Badger, Matthew S. Dreier, Barbara Rehermann, Regina Umarova, Kevin D. Hall, Benedikt Hild, Claire E Thefaine, Ji Hoon Oh, Giorgio Trinchieri, John A. McCulloch, and Juen Guo
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business.industry ,Endocrinology, Diabetes and Metabolism ,Fatty liver ,Medizin ,Physiology ,Cell Biology ,Disease ,medicine.disease ,Obesity ,Article ,medicine.anatomical_structure ,Physiology (medical) ,Brown adipose tissue ,Internal Medicine ,Medicine ,Humans ,Microbiome ,medicine.symptom ,Metabolic syndrome ,business ,Weight gain ,Hormone - Abstract
Obesity and its consequences are among the greatest challenges in healthcare. The gut microbiome is recognized as a key factor in the pathogenesis of obesity. Using a mouse model, we show here that a wild-derived microbiome protects against excessive weight gain, severe fatty liver disease and metabolic syndrome during a 10-week course of high-fat diet. This phenotype is transferable only during the first weeks of life. In adult mice, neither transfer nor severe disturbance of the wild-type microbiome modifies the metabolic response to a high-fat diet. The protective phenotype is associated with increased secretion of metabolic hormones and increased energy expenditure through activation of brown adipose tissue. Thus, we identify a microbiome that protects against weight gain and its negative consequences through metabolic programming in early life. Translation of these results to humans may identify early-life therapeutics that protect against obesity.
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- 2021
8. Neonatal exposure to a wild-derived microbiome protects mice against diet-induced obesity
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Benedikt, Hild, Matthew S, Dreier, Ji Hoon, Oh, John A, McCulloch, Jonathan H, Badger, Juen, Guo, Claire E, Thefaine, Regina, Umarova, Kevin D, Hall, Oksana, Gavrilova, Stephan P, Rosshart, Giorgio, Trinchieri, and Barbara, Rehermann
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Time Factors ,Host Microbial Interactions ,Microbiota ,Environmental Exposure ,Diet, High-Fat ,Weight Gain ,Animal Feed ,Diet ,Gastrointestinal Microbiome ,Disease Models, Animal ,Mice ,Animals ,Disease Susceptibility ,Obesity ,Energy Metabolism ,Disease Resistance - Abstract
Obesity and its consequences are among the greatest challenges in healthcare. The gut microbiome is recognized as a key factor in the pathogenesis of obesity. Using a mouse model, we show here that a wild-derived microbiome protects against excessive weight gain, severe fatty liver disease and metabolic syndrome during a 10-week course of high-fat diet. This phenotype is transferable only during the first weeks of life. In adult mice, neither transfer nor severe disturbance of the wild-type microbiome modifies the metabolic response to a high-fat diet. The protective phenotype is associated with increased secretion of metabolic hormones and increased energy expenditure through activation of brown adipose tissue. Thus, we identify a microbiome that protects against weight gain and its negative consequences through metabolic programming in early life. Translation of these results to humans may identify early-life therapeutics that protect against obesity.
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- 2020
9. Liver-Resident Bystander CD8
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Helenie, Kefalakes, Xylia J, Horgan, Min Kyung, Jung, Georgios, Amanakis, Devika, Kapuria, Fabian J, Bolte, David E, Kleiner, Christopher, Koh, Theo, Heller, and Barbara, Rehermann
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Adult ,Male ,Hepatitis D, Chronic ,Adaptive Immunity ,CD8-Positive T-Lymphocytes ,Lymphocyte Activation ,Cell Degranulation ,Mucosal-Associated Invariant T Cells ,Article ,Young Adult ,Cell Line, Tumor ,Humans ,Aged ,Natural Cytotoxicity Triggering Receptor 3 ,Middle Aged ,Immunity, Innate ,Killer Cells, Natural ,Phenotype ,Liver ,NK Cell Lectin-Like Receptor Subfamily K ,Case-Control Studies ,Host-Pathogen Interactions ,Disease Progression ,Cytokines ,Female ,Hepatitis Delta Virus ,Immunologic Memory - Abstract
BACKGROUND & AIMS: The hepatitis D virus (HDV) causes the most severe form of chronic hepatitis, often progressing to cirrhosis within 5–10 years. There is no curative treatment and the mechanisms underlying the accelerated liver disease progression are unknown. METHODS: Innate and adaptive immune responses were studied in blood and liver of 24 HDV-infected patients and 30 uninfected controls by multiparameter flow cytometry in correlation with disease severity and stage. RESULTS: The two main intrahepatic innate immune-cell populations, MAIT cells and NK cells, were reduced in the livers of HDV-infected patients compared to those of uninfected controls but were more frequently activated in the liver compared to the blood. Most intrahepatic CD8(+) T cells were memory cells or terminal effector memory cells, and the majority of activated and degranulating (CD107a(+)) HDV-specific and total CD8(+) T cells were liver-resident (CD69(+)CXCR6(+)). Unsupervised analysis of flow cytometry data identified an activated, memory-like, tissue-resident HDV-specific CD8(+) T-cell cluster with expression of innate-like NKp30 and NKG2D receptors. The size of this population correlated with liver enzyme activity (r=1.0). NKp30 and NKG2D expression extended beyond the HDV-specific to the total intrahepatic CD8(+) T-cell population suggesting global bystander activation. This was supported by the correlations between NKG2D expression and degranulation of intrahepatic CD8(+) T cells and between frequency of degranulating CD8(+) T cells and liver enzyme activity, and APRI score and by in vitro demonstration of cytokine-induced NKDG2D-dependent cytotoxicity. CONCLUSION: Antigen-nonspecific activation of liver-resident CD8(+) T cells may contribute to inflammation and disease stage in HDV infection.
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- 2020
10. Virus-Induced Interferon Regulates the Urea Cycle
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Barbara Rehermann and Akira Nishio
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0301 basic medicine ,Proteomics ,T-Lymphocytes ,Immunology ,immunometabolism ,CD8 T cells ,virus ,Biology ,liver ,Antiviral Agents ,Virus ,Article ,Transcriptome ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Metabolomics ,Interferon ,medicine ,urea cycle ,hepatocyte ,Immunology and Allergy ,Animals ,Lymphocytic choriomeningitis virus ,Urea ,hepatitis ,Liver injury ,Metabolism ,medicine.disease ,infection ,Cell biology ,interferons ,030104 developmental biology ,Infectious Diseases ,inflammation ,030220 oncology & carcinogenesis ,Urea cycle ,Interferon Type I ,Interferon type I ,medicine.drug - Abstract
Summary Infections induce complex host responses linked to antiviral defense, inflammation, and tissue damage and repair. We hypothesized that the liver, as a central metabolic hub, may orchestrate systemic metabolic changes during infection. We infected mice with chronic lymphocytic choriomeningitis virus (LCMV), performed RNA sequencing and proteomics of liver tissue, and integrated these data with serum metabolomics at different infection phases. Widespread reprogramming of liver metabolism occurred early after infection, correlating with type I interferon (IFN-I) responses. Viral infection induced metabolic alterations of the liver that depended on the interferon alpha/beta receptor (IFNAR1). Hepatocyte-intrinsic IFNAR1 repressed the transcription of metabolic genes, including Otc and Ass1, which encode urea cycle enzymes. This led to decreased arginine and increased ornithine concentrations in the circulation, resulting in suppressed virus-specific CD8+ T cell responses and ameliorated liver pathology. These findings establish IFN-I-induced modulation of hepatic metabolism and the urea cycle as an endogenous mechanism of immunoregulation. Video Abstract, Graphical Abstract, Highlights • Chronic viral infection causes long-term transcriptome and proteome changes in the liver • Hepatocyte-intrinsic type I interferon (IFN-I) signaling regulates hepatic metabolism • IFN-I signaling reprograms the urea cycle in hepatocytes and alters serum metabolites • Serum levels of arginine and ornithine modulate T cell responses and pathology, The liver is a central regulator of metabolism, but how infection-induced changes in liver metabolism affect immune responses and pathology remains enigmatic. Lercher et al. demonstrate that hepatocyte-intrinsic type I interferon (IFN-I) represses metabolism during chronic viral infection. Specifically, IFN-I disrupts the urea cycle in hepatocytes, altering serum arginine and ornithine levels, which dampen antiviral T cells responses and liver pathology.
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- 2020
11. Clearance of pegylated interferon by Kupffer cells limits NK cell activation and therapy response of patients with HBV infection
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Fabian J. Bolte, Marc G. Ghany, Zu-Xi Yu, Heiyoung Park, Nana Park, Kristin Valdez, Kazuyo Takeda, Barbara Rehermann, and Akira Nishio
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0301 basic medicine ,HBsAg ,Hepatitis B virus ,Kupffer Cells ,Inflammation ,Antiviral Agents ,Virus ,Polyethylene Glycols ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Hepatitis B, Chronic ,Pegylated interferon ,medicine ,Humans ,biology ,business.industry ,technology, industry, and agriculture ,Cancer ,General Medicine ,medicine.disease ,Recombinant Proteins ,Killer Cells, Natural ,030104 developmental biology ,Treatment Outcome ,Immunoglobulin M ,Immunology ,biology.protein ,030211 gastroenterology & hepatology ,medicine.symptom ,business ,Cell activation ,medicine.drug - Abstract
Pegylated interferon-α (PEG-IFN-α), where IFN-α is attached to polyethylene glycol (PEG), is an approved treatment for chronic hepatitis B virus (HBV) infection, a disease that causes liver-related morbidity and mortality in 257 million people worldwide. It is unknown why only a minority of patients respond to PEG-IFN-α. Using sequential blood samples and liver biopsies of patients with chronic HBV infection before, during, and after PEG-IFN-α treatment, we find that patients with early natural killer (NK) cell activation after PEG-IFN-α injection experienced greater liver inflammation, lysis of HBV-infected hepatocytes, and hepatitis B surface antigen (HBsAg) decline than those without. NK cell activation was associated with induction of interferon-stimulated genes and determined by PEG-IFN-α pharmacokinetics. Patients with delayed increases in PEG-IFN-α concentrations had greater amounts of PEG-specific immunoglobulin M (IgM) immune complexes in the blood and more PEG and IgM detected in the liver than patients with rapid increase in PEG-IFN-α concentration. This was associated with reduced NK cell activation. These results indicate that the immunomodulatory functions of PEG-IFN-α, particularly activation of NK cells, play a pivotal role in the response to treatment and further demonstrate that these functions are affected by PEG-IFN-α pharmacokinetics. Accelerated clearance of antibody-complexed pegylated drugs by Kupffer cells may be important beyond the field of HBV therapeutics. Thus, these findings may contribute to improving the efficacy of pegylated drugs that are now being developed for other chronic diseases and cancer.
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- 2020
12. Author response: Discovery of several thousand highly diverse circular DNA viruses
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Olga Pletnikova, John Doorbar, Siddharth R. Krishnamurthy, Christopher B. Buck, Jason M. Brenchley, Ben Bolduc, Matthew B. Sullivan, Michael J. Tisza, Barbara Rehermann, David H. McDermott, Arvind Varsani, Yuk-Ying S. Pang, Nicole L. Welch, Stephan P. Rosshart, Blake A Ta'ala, Gabriel J. Starrett, Jessica L. Whited, Alberto Peretti, Diana V. Pastrana, Juan C. Troncoso, Brittany Stewart, Patricia A. Pesavento, Bess M. Miller, Philip M. Murphy, Susan M. Resnick, and Anca M. Segall
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Circular DNA ,Computational biology ,Biology - Published
- 2020
13. Infection Trains the Microbiota for Enhanced Resistance to Pathogens
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Julia A. Segre, Apollo Stacy, Choon Kiat Sim, Barbara Rehermann, Benedikt Hild, Vinicius Andrade-Oliveira, Ji Hoon Oh, Yasmine Belkaid, Giorgio Trinchieri, P. Juliana Perez-Chaparro, and John A. McCulloch
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Taurine ,biology ,Cellular respiration ,Prebiotic ,medicine.medical_treatment ,Colonisation resistance ,Gut flora ,biology.organism_classification ,digestive system ,Microbiology ,chemistry.chemical_compound ,Immune system ,chemistry ,medicine ,Microbiome ,Pathogen - Abstract
The microbiota shields the host against infections in a process known as colonization resistance. How infections themselves shape this fundamental process remains largely unknown. Here, we show that gut microbiota from previously infected hosts display enhanced resistance to infections. This long-term functional remodeling is associated with altered bile acid metabolism leading to the expansion of taxa that utilize the sulfonic acid taurine. Notably, supplying exogenous taurine alone is sufficient to induce this alteration in microbiota function and enhance resistance. Mechanistically, taurine potentiates the microbiota’s production of sulfide, an inhibitor of cellular respiration, which is key to host invasion by numerous pathogens. As such, pharmaceutical sequestration of sulfide perturbs the microbiota’s composition and promotes pathogen invasion. Together, this work reveals a process, akin to the immune system’s capacity for training, by which the host can deploy taurine as a prebiotic to nourish and educate the microbiota, promoting its resistance to infection.
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- 2020
14. Improving Natural Product Research Translation: from Source to Clinical Trial
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Jacqueline M. Stephens, Barbara C. Sorkin, Mahtab Jafari, Paula N. Brown, Naomi K. Fukagawa, D. Craig Hopp, Mario G. Ferruzzi, Kathleen R. Pritchett-Corning, Jeffrey Paul, Hervé Tiriac, Daniel Lakens, Bruce Barrett, Floyd H. Chilton, Sara K. Quinney, Dan Xi, Barbara Rehermann, John B. MacMillan, Freddie Ann Hoffman, Nisha S. Sipes, David O. Meltzer, Christopher S. Coffey, Adam J. Kuszak, Frederic D. Bushman, Kenneth D.R. Setchell, D. Lansing Taylor, Gregory Bloss, Giovanna Zappalà, Marco Pahor, Michael A. Walters, Mairead Kiely, Steven J. Casper, Guido F. Pauli, and Human Technology Interaction
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0301 basic medicine ,Prioritization ,Predictive validity ,medicine.medical_specialty ,Biochemistry & Molecular Biology ,Biomedical ,Computer science ,Physiology ,Medical Physiology ,Drug Evaluation, Preclinical ,Ethnobotany ,SDG 3 – Goede gezondheid en welzijn ,Biochemistry ,Article ,Value of information ,dietary supplements ,model systems ,Translational Research, Biomedical ,03 medical and health sciences ,0302 clinical medicine ,rigor and replicability ,SDG 3 - Good Health and Well-being ,Clinical Research ,Translational Research ,Complementary and Integrative Health ,Genetics ,medicine ,Animals ,Humans ,clinical predictive validity ,Translational Medical Research ,Molecular Biology ,Biological Products ,Public health ,Preclinical ,value of information ,Clinical trial ,030104 developmental biology ,Good Health and Well Being ,Risk analysis (engineering) ,Drug Evaluation ,Research questions ,Biochemistry and Cell Biology ,030217 neurology & neurosurgery ,Biotechnology - Abstract
While great interest in health effects of natural product (NP) including dietary supplements and foods persists, promising preclinical NP research is not consistently translating into actionable clinical trial (CT) outcomes. Generally considered the gold standard for assessing safety and efficacy, CTs, especially phase III CTs, are costly and require rigorous planning to optimize the value of the information obtained. More effective bridging from NP research to CT was the goal of a September,2018transdisciplinaryworkshop. Participants emphasized that replicability and likelihood of successful translation depend on rigor in experimental design, interpretation, and reporting across the continuum of NP research. Discussions spanned good practices for NP characterization and quality control; use and interpretation of models (computational through in vivo) with strong clinical predictive validity; controls for experimental artefacts, especially for in vitro interrogation of bioactivity and mechanisms of action; rigorous assessment and interpretation of prior research; transparency in all reporting; and prioritization of research questions. Natural product clinical trials prioritized based on rigorous, convergent supporting data and current public health needs are most likely to be informative and ultimately affect public health. Thoughtful, coordinated implementation of these practices should enhance the knowledge gained from future NP research.
- Published
- 2019
15. Keratinocyte-intrinsic MHCII expression controls microbiota-induced Th1 cell responses
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Jonathan L. Linehan, Paula Juliana Pérez-Chaparro, Barbara Rehermann, Oliver J. Harrison, Ivan Vujkovic-Cvijin, Vanja Lazarevic, Michael G. Constantinides, Samira Tamoutounour, Julie Deckers, Seong-Ji Han, Nicolas Bouladoux, Stephan P. Rosshart, C. Hurabielle, Verena M. Link, and Yasmine Belkaid
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Keratinocytes ,Staphylococcus aureus ,Lymphocyte ,T cell ,Antigen presentation ,Genes, MHC Class II ,Biology ,Interferon-gamma ,Mice ,Immune system ,Candida albicans ,medicine ,Staphylococcus epidermidis ,Skin immunity ,Animals ,Symbiosis ,MHC class II ,Antigen Presentation ,Multidisciplinary ,Host Microbial Interactions ,Microbiota ,Innate lymphoid cell ,Histocompatibility Antigens Class II ,Th1 Cells ,Biological Sciences ,Cell biology ,Specific Pathogen-Free Organisms ,Mice, Inbred C57BL ,medicine.anatomical_structure ,Organ Specificity ,Radiation Chimera ,biology.protein ,Epidermis ,Keratinocyte - Abstract
The cross-talk between the microbiota and the immune system plays a fundamental role in the control of host physiology. However, the tissue-specific factors controlling this dialogue remain poorly understood. Here we demonstrate that T cell responses to commensal colonization are associated with the development of organized cellular clusters within the skin epithelium. These organized lymphocyte clusters are surrounded by keratinocytes expressing a discrete program associated with antigen presentation and antimicrobial defense. Notably, IL-22–mediated keratinocyte-intrinsic MHC class II expression was required for the selective accumulation of commensal-induced IFN-γ, but not IL-17A–producing CD4 + T cells within the skin. Taking these data together, this work uncovers an unexpected role for MHC class II expression by keratinocytes in the control of homeostatic type 1 responses to the microbiota. Our findings have important implications for the understanding of the tissue-specific rules governing the dialogue between a host and its microbiota.
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- 2019
16. Baseline Intrahepatic and Peripheral Innate Immunity are Associated with Hepatitis C Virus Clearance During Direct‐Acting Antiviral Therapy
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Nicolaas H. Fourie, Barbara Rehermann, Heiyoung Park, Maggie Cam, Daniel Suarez, Hawwa Alao, T. Jake Liang, Chithra Keembiyehetty, Wendy A. Henderson, Qisheng Li, Elisavet Serti, Marc G. Ghany, Elizabeth C. Wright, and Fang Zhang
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0301 basic medicine ,Daclatasvir ,Hepatology ,medicine.diagnostic_test ,business.industry ,Hepatitis C virus ,Ribavirin ,virus diseases ,medicine.disease_cause ,Viral Breakthrough ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,chemistry ,Interferon ,Immunity ,Biopsy ,Immunology ,medicine ,Asunaprevir ,business ,medicine.drug - Abstract
Hepatitis C virus (HCV) infection induces interferon (IFN)-stimulated genes (ISGs) and downstream innate immune responses. This study investigated whether baseline and on-treatment differences in these responses predict response versus virological breakthrough during therapy with direct-acting antivirals (DAAs). Thirteen HCV genotype 1b-infected patients who had previously failed a course of pegylated IFN/ribavirin were retreated with asunaprevir/daclatasvir for 24 weeks. After pretreatment biopsy, patients were randomized to undergo a second biopsy at week 2 or 4 on therapy. Microarray and NanoString analyses were performed on paired liver biopsies and analyzed using linear mixed models. As biomarkers for peripheral IFN responses, peripheral blood natural killer cells were assessed for phosphorylated signal transducer and activator of transcription 1 (pSTAT1) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression and degranulation. Nine of 13 (69%) patients achieved sustained virological response at 12 weeks off therapy (SVR12), and 4 experienced virological breakthroughs between weeks 4 and 12. Patients who achieved SVR12 displayed higher ISG expression levels in baseline liver biopsies and a higher frequency of pSTAT1 and TRAIL-expressing, degranulating natural killer cells in baseline blood samples than those who experienced virological breakthrough. Comparing gene expression levels from baseline and on-therapy biopsies, 408 genes (±1.2-fold, P < 0.01) were differentially expressed. Genes down-regulated on treatment were predominantly ISGs. Down-regulation of ISGs was rapid and correlated with HCV RNA suppression. Conclusion: An enhanced IFN signature is observed at baseline in liver and blood of patients who achieve SVR12 compared to those who experience a virological breakthrough; the findings suggest that innate immunity may contribute to clearance of HCV during DAA therapy by preventing the emergence of resistance-associated substitutions that lead to viral breakthrough during DAA therapy.
- Published
- 2018
17. Inflammation drives an altered phenotype of mucosal-associated invariant T cells in chronic hepatitis D virus infection
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Barbara Rehermann and Helenie Kefalakes
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Inflammation ,Hepatitis D, Chronic ,Hepatology ,business.industry ,viruses ,MAIT Cells ,virus diseases ,Mucosal associated invariant T cell ,biochemical phenomena, metabolism, and nutrition ,medicine.disease ,Phenotype ,Hepatitis D ,Mucosal-Associated Invariant T Cells ,Article ,Virus ,Chronic hepatitis ,Immunology ,Humans ,Medicine ,Hepatitis Delta Virus ,medicine.symptom ,business ,Viral hepatitis - Abstract
BACKGROUND & AIMS: Hepatitis delta virus (HDV) infection is the most severe form of viral hepatitis. Although HDV-associated liver disease is considered immune-mediated, adaptive immune responses against HDV are weak. Thus, the role of several other cell-mediated mechanisms such as those driven by mucosa-associated invariant T (MAIT) cells, a group of innate-like T cells being highly enriched in the human liver, have not been extensively studied in clinical HDV infection. METHODS: MAIT cells from a sizeable cohort of chronic HDV patients were analyzed ex vivo and in vitro after stimulation. Results were compared with MAIT cells from HBV mono-infected patients and healthy controls. RESULTS: Circulating MAIT cells were dramatically decreased in the peripheral blood of HDV-infected patients. Signs of decline were also observed in the liver. In contrast, only a modest decrease of circulating MAIT cells was noted in HBV mono-infection. Unsupervised high-dimensional analysis of residual circulating MAIT cells in chronic HDV infection revealed the appearance of a compound phenotype of CD38(hi)PD-1(hi)CD28(lo)CD127(lo)PLZF(lo)Eomes(lo)Helios(lo) cells indicative of activation. Corroborating these results, MAIT cells exhibited a functionally impaired responsiveness. In parallel to MAIT cell loss, HDV-infected patients exhibited signs of monocyte activation and increased levels of pro-inflammatory cytokines IL-12 and IL-18. In vitro, IL-12 and IL-18 induced an activated MAIT cell phenotype similar to the one observed ex vivo in HDV-infected patients. These cytokines also promoted MAIT cell death, suggesting that they may contribute to MAIT cell activation and subsequent loss during HDV infection. CONCLUSIONS: These results suggest that chronic HDV infection engages the MAIT cell compartment causing activation, functional impairment, and subsequent progressive loss as the HDV-associated liver disease progresses.
- Published
- 2019
18. Liver-Resident Bystander CD8+ T Cells Contribute to Liver Disease Pathogenesis in Chronic Hepatitis D Virus Infection
- Author
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Fabian J. Bolte, Theo Heller, Christopher Koh, Barbara Rehermann, David E. Kleiner, Min Kyung Jung, Georgios Amanakis, Xylia J. Horgan, Devika Kapuria, and Helenie Kefalakes
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Cirrhosis ,Hepatology ,Degranulation ,Gastroenterology ,Mucosal associated invariant T cell ,Biology ,NKG2D ,medicine.disease ,Natural killer cell ,Liver disease ,Immune system ,medicine.anatomical_structure ,Immunology ,medicine ,Cytotoxic T cell ,Hepatitis D virus ,CD8 - Abstract
Background & Aims The hepatitis D virus (HDV) causes the most severe form of chronic hepatitis, often progressing to cirrhosis within 5 to 10 years. There is no curative treatment, and the mechanisms underlying the accelerated liver disease progression are unknown. Methods Innate and adaptive immune responses were studied in blood and liver of 24 patients infected with HDV and 30 uninfected controls by multiparameter flow cytometry in correlation with disease severity and stage. Results The 2 main intrahepatic innate immune-cell populations, mucosal-associated invariant T cells and natural killer (NK) cells, were reduced in the livers of patients infected with HDV compared with those of uninfected controls but were more frequently activated in the liver compared with the blood. Most intrahepatic cluster of differentiation (CD) 8-positive (CD8+) T cells were memory cells or terminal effector memory cells, and most of the activated and degranulating (CD107a+) HDV-specific and total CD8+ T cells were liver-resident (CD69+C-X-C motif chemokine receptor 6+). Unsupervised analysis of flow cytometry data identified an activated, memory-like, tissue-resident HDV-specific CD8+ T-cell cluster with expression of innate-like NK protein 30 (NKp30) and NK group 2D (NKG2D) receptors. The size of this population correlated with liver enzyme activity (r = 1.0). NKp30 and NKG2D expression extended beyond the HDV-specific to the total intrahepatic CD8+ T-cell population, suggesting global bystander activation. This was supported by the correlations between (i) NKG2D expression with degranulation of intrahepatic CD8+ T cells, (ii) frequency of degranulating CD8+ T cells with liver enzyme activity and the aspartate aminotransferase-to-platelet ratio index score, and by the in vitro demonstration of cytokine-induced NKG2D-dependent cytotoxicity. Conclusion Antigen-nonspecific activation of liver-resident CD8+ T cells may contribute to inflammation and disease stage in HDV infection.
- Published
- 2021
19. Hepatitis B virus evades innate immunity of hepatocytes but activates cytokine production by macrophages
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Peter Block, Xiaoming Cheng, Kazuaki Chayama, Michelle T. Chung, Yuchen Xia, Elisavet Serti, Barbara Rehermann, and T. Jake Liang
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0301 basic medicine ,Hepatitis B virus ,medicine.medical_treatment ,Biology ,medicine.disease_cause ,Article ,Virus ,03 medical and health sciences ,Immune system ,Interferon ,Immunity ,medicine ,Humans ,Innate immune system ,Hepatology ,Macrophages ,Pattern recognition receptor ,virus diseases ,Hep G2 Cells ,Hepatitis B ,Immunity, Innate ,digestive system diseases ,030104 developmental biology ,Cytokine ,Host-Pathogen Interactions ,Immunology ,Hepatocytes ,Cytokines ,Interferons ,medicine.drug - Abstract
Hepatitis B virus (HBV) infects hepatocytes specifically and causes immune mediated liver damage. How HBV interacts with the innate immunity at the early phase of infection, either with the hepatocytes or other cells in the liver remains controversial. To address this question, we utilized various cell culture models and humanized Alb-uPA/SCID mice. All these models were unable to mount an interferon (IFN) response despite robust HBV replication. To elucidate the mechanisms involved in the lack of IFN response, we examined whether HBV actively inhibits innate immune functions of hepatocytes. By treating HBV infected cells with known inducers of IFN signaling pathway, we observed no alteration of either sensing or downstream IFN response by HBV. We showed that the DNA innate sensing pathways are poorly active in hepatocytes, consistent with the muted innate immune recognition of HBV. Upon exposure to high-level HBV, macrophages could be activated with increased inflammatory cytokine expressions. Conclusion: HBV behaves like a “stealth” virus and is not sensed by nor actively interferes with the intrinsic innate immunity of the infected hepatocytes. Macrophages are capable of sensing HBV but require exposure to high HBV titers, potentially explaining the long “window period” during acute infection and HBV's propensity to chronic infection. This article is protected by copyright. All rights reserved.
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- 2017
20. Use of Current and New Endpoints in the Evaluation of Experimental Hepatitis B Therapeutics
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Brian J. McMahon, Timothy M. Block, Marion G. Peters, Barbara Rehermann, and Stephen Locarnini
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0301 basic medicine ,Microbiology (medical) ,Drug ,Oncology ,medicine.medical_specialty ,Endpoint Determination ,media_common.quotation_subject ,Review Article ,Circular DNA ,Pharmacology ,medicine.disease_cause ,Hepatitis b surface antigen ,03 medical and health sciences ,Hepatitis B, Chronic ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,media_common ,Hepatitis B virus ,business.industry ,Surrogate endpoint ,virus diseases ,Hepatitis B ,medicine.disease ,digestive system diseases ,Treatment Outcome ,030104 developmental biology ,Infectious Diseases ,030211 gastroenterology & hepatology ,business ,Biomarkers - Abstract
New hepatitis B virus (HBV) therapies are expected to have breakthrough benefit for patients. HBV functional cure is sustained hepatitis B surface antigen loss and anti-HBs gain, with normalization of serum aminotransferases off therapy. Virologic or complete cure additionally includes loss of HBV covalently closed circular DNA. Currently available endpoints of therapy are inadequate to evaluate the efficacy of many of the new therapeutics. Therefore, either new ways of using the existing virologic endpoints and laboratory values or entirely new biomarkers are needed. In this review, we discuss the currently used endpoints, potential new endpoints, as well as what new markers are needed to assess the ability of HBV therapeutics to achieve functional and virologic cure in various phases of HBV infection. In addition, we discuss how patient selection from differing phases of HBV impacts the choice of HBV drug(s) needed to achieve cure.
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- 2017
21. Mature peritoneal macrophages take an avascular route into the injured liver and promote tissue repair
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Barbara Rehermann
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0301 basic medicine ,Pathology ,medicine.medical_specialty ,Article ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Text mining ,Cell Movement ,GATA6 Transcription Factor ,Leukocytes ,Humans ,Animals ,Medicine ,Inflammation ,Mice, Knockout ,Wound Healing ,Hepatology ,business.industry ,Macrophages ,Tissue repair ,Specific Pathogen-Free Organisms ,Disease Models, Animal ,030104 developmental biology ,Liver ,030220 oncology & carcinogenesis ,Macrophages, Peritoneal ,business - Abstract
A key feature of inflammation is the timely recruitment of leukocytes, including monocytes, from blood into tissues, the latter maturing into macrophages over a period of 2-3 days. Using multi-channel spinning disk microscopy, we identified a rapid pathway of macrophage recruitment into an injured organ via a non-vascular route requiring no maturation from monocytes. In response to a sterile injury in liver, a reservoir of fully mature F4/80(hi)GATA6(+) peritoneal cavity macrophages rapidly invaded into afflicted tissue via direct recruitment across the mesothelium. The invasion was dependent on CD44 and DAMP molecule ATP and resulted in rapid replication and switching of macrophage toward an alternatively activated phenotype. These macrophages dismantled the nuclei of necrotic cells releasing DNA and forming a cover across the injury site. Rapid invasion of mature macrophages from body cavity with capacity for induction of reparative phenotype may impact altered tissues ranging from trauma to infections to cancer. VIDEO ABSTRACT.
- Published
- 2016
22. The role of genetics in hepatic fibrosis among hepatitis C virus patients
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Thomas R. O'Brien, Heiyoung Park, and Barbara Rehermann
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0301 basic medicine ,Hepatology ,biology ,business.industry ,Hepatitis C virus ,Hepacivirus ,Disease progression ,Hepatitis C ,medicine.disease_cause ,medicine.disease ,biology.organism_classification ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Genotype ,Immunology ,medicine ,030211 gastroenterology & hepatology ,Hepatic fibrosis ,business ,Liver pathology - Published
- 2018
23. Discovery of several thousand highly diverse circular DNA viruses
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Barbara Rehermann, Susan M. Resnick, Anca M. Segall, Ben Bolduc, Blake A Ta'ala, Jason M. Brenchley, Patricia A. Pesavento, Arvind Varsani, Diana V. Pastrana, Nicole L. Welch, Philip M. Murphy, Olga Pletnikova, David H. McDermott, Yuk Ying S. Pang, Juan C. Troncoso, Jessica L. Whited, Brittany Stewart, John Doorbar, Bess M. Miller, Stephan P. Rosshart, Alberto Peretti, Gabriel J. Starrett, Matthew B. Sullivan, Siddharth R. Krishnamurthy, Michael J. Tisza, Christopher B. Buck, Pastrana, Diana V [0000-0002-8084-5665], Whited, Jessica L [0000-0002-3709-6515], Miller, Bess [0000-0002-9868-5436], Varsani, Arvind [0000-0003-4111-2415], Buck, Christopher B [0000-0003-3165-8094], and Apollo - University of Cambridge Repository
- Subjects
0301 basic medicine ,Viral metagenomics ,viruses ,microbiome ,Genome ,viral evolution ,RefSeq ,2.2 Factors relating to the physical environment ,Viral ,Biology (General) ,Aetiology ,Microbiology and Infectious Disease ,General Neuroscience ,General Medicine ,DNA Virus Infections ,Virus ,Infectious Diseases ,Capsid ,Viral evolution ,GenBank ,Medicine ,DNA, Circular ,Infection ,Recombination ,Biotechnology ,Research Article ,QH301-705.5 ,Science ,infectious disease ,030106 microbiology ,Circular ,Computational biology ,Circular DNA ,virus ,Genome, Viral ,Biology ,ENCODE ,General Biochemistry, Genetics and Molecular Biology ,DNA sequencing ,03 medical and health sciences ,Animals ,Humans ,Human virome ,Gene ,Evolutionary Biology ,metagenomics ,General Immunology and Microbiology ,evolutionary biology ,microbiology ,DNA Viruses ,Molecular Sequence Annotation ,DNA ,030104 developmental biology ,Metagenomics ,FOS: Biological sciences ,DNA, Viral ,Capsid Proteins ,Biochemistry and Cell Biology ,Software - Abstract
Although millions of distinct virus species likely exist, only approximately 9000 are catalogued in GenBank's RefSeq database. We selectively enriched for the genomes of circular DNA viruses in over 70 animal samples, ranging from nematodes to human tissue specimens. A bioinformatics pipeline, Cenote-Taker, was developed to automatically annotate over 2500 complete genomes in a GenBank-compliant format. The new genomes belong to dozens of established and emerging viral families. Some appear to be the result of previously undescribed recombination events between ssDNA and ssRNA viruses. In addition, hundreds of circular DNA elements that do not encode any discernable similarities to previously characterized sequences were identified. To characterize these ‘dark matter’ sequences, we used an artificial neural network to identify candidate viral capsid proteins, several of which formed virus-like particles when expressed in culture. These data further the understanding of viral sequence diversity and allow for high throughput documentation of the virosphere., eLife digest When scientists hunt for new DNA sequences, sometimes they get a lot more than they bargained for. Such is the case in metagenomic surveys, which analyze not just DNA of a particular organism, but all the DNA in an environment at large. A vexing problem with these surveys is the overwhelming number of DNA sequences detected that are so different from any known microbe that they cannot be classified using traditional approaches. However, some of these “known unknowns” are undoubtedly viral sequences, because only a fraction of the enormous diversity of viruses has been characterized. This “viral dark matter” is a major obstacle for those studying viruses. This led Tisza et al. to attempt to classify some of the unknown viral sequences in their metagenomic surveys. The search, which specifically focused on viruses with circular DNA genomes, detected over 2,500 circular viral genomes. Intensive analysis revealed that many of these genomes had similar makeup to previously discovered viruses, but hundreds of them were totally different from any known virus, based on typical methods of comparison. Computational analysis of genes that were conserved among some of these brand-new circular sequences often revealed virus-like features. Experiments on a few of these genes showed that they encoded proteins capable of forming particles reminiscent of characteristic viral shells, implying that these new sequences are indeed viruses. Tisza et al. have added the 2,500 newly characterized viral sequences to the publicly accessible GenBank database, and the sequences are being considered for the more authoritative RefSeq database, which currently contains around 9,000 complete viral genomes. The expanded databases will hopefully now better equip scientists to explore the enormous diversity of viruses and help medics and veterinarians to detect disease-causing viruses in humans and other animals.
- Published
- 2019
24. Improving Natural Product Research Translation: from Source to Clinical Trial
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Barbara C Sorkin, Adam J Kuszak, Naomi K Fukagawa, Freddie Ann Hoffman, Mahtab Jafari, Bruce Barrett, Paula N. Brown, Frederic D. Bushman, Steven Casper, Floyd H. Chilton, Christopher S. Coffey, Mario G. Ferruzzi, D. Craig Hopp, Mairead Kiely, Daniel Lakens, John B. MacMillan, David Meltzer, Marco Pahor, Jeffrey Paul, Kathleen Pritchett-Corning, Sara Quinney, Barbara Rehermann, Kenneth D.R. Setchell, Nisha S. Sipes, Jacqueline M. Stephens, D. Lansing Taylor, Herve Tiriac, Michael Walters, Dan Xi, Giovanna Zappala, and Guido Pauli
- Subjects
NutriXiv|Medicine and Health Sciences ,bepress|Medicine and Health Sciences ,NutriXiv|Medicine and Health Sciences|Public Health ,bepress|Medicine and Health Sciences|Public Health - Abstract
While great interest in health effects of natural product (NP) foods and dietary supplements persists, promising preclinical NP research is not consistently translating into actionable clinical trial (CT) outcomes. Generally considered the gold standard for assessing safety and efficacy, CTs,especially Phase III CTs, are costly and require rigorous planning to optimize the value of the information obtained. More effective bridging from NP research to CT was the goal of a September, 2018 transdisciplinary workshop. Participants emphasized that replicability and likelihood of successful translation depend on rigor in experimental design, interpretation, and reporting across the continuum of NP research. Discussions spanned good practices for: NPcharacterization and quality control; use and interpretation of models (computational through in vivo) with strong clinical predictive validity; controls for experimental artefacts, especially for in vitro interrogation of bioactivity and mechanisms of action; rigorous assessment and interpretation of prior research; transparency in all reporting; and prioritization of research questions. NPCTsprioritized based on rigorous, convergent supporting data and current public health needs are most likely to be informative and ultimately affect public health. Thoughtful, coordinated implementation of these practices should enhance the knowledge gained from future NP research.
- Published
- 2019
25. A global scientific strategy to cure hepatitis B
- Author
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Peter A Revill, Francis V Chisari, Joan M Block, Maura Dandri, Adam J Gehring, Haitao Guo, Jianming Hu, Anna Kramvis, Pietro Lampertico, Harry L A Janssen, Massimo Levrero, Wenhui Li, T Jake Liang, Seng-Gee Lim, Fengmin Lu, M Capucine Penicaud, John E Tavis, Robert Thimme, Fabien Zoulim, Patrick Arbuthnot, Andre Boonstra, Kyong-Mi Chang, Per-Jei Chen, Dieter Glebe, Luca G. Guidotti, Jacques Fellay, Carlo Ferrari, Louis Jansen, Daryl T Y Lau, Anna S Lok, Mala K Maini, William Mason, Gail Matthews, Dimitrios Paraskevis, Jörg Petersen, Barbara Rehermann, Eui-Cheol Shin, Alex Thompson, Florian van Bömmel, Fu-Sheng Wang, Koichi Watashi, Hung-Chih Yang, Zhenghong Yuan, Man-Fung Yuen, Timothy Block, Veronica Miller, Ulrike Protzer, Christian Bréchot, Stephen Locarnini, Marion G Peters, Raymond F Schinazi, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Revill, P. A., Chisari, F. V., Block, J. M., Dandri, M., Gehring, A. J., Guo, H., Hu, J., Kramvis, A., Lampertico, P., Janssen, H. L. A., Levrero, M., Li, W., Liang, T. J., Lim, S. -G., Lu, F., Penicaud, M. C., Tavis, J. E., Thimme, R., Arbuthnot, P., Boonstra, A., Chang, K. -M., Chen, P. -J., Glebe, D., Guidotti, L. G., Fellay, J., Ferrari, C., Jansen, L., Lau, D. T. Y., Lok, A. S., Maini, M. K., Mason, W., Matthews, G., Paraskevis, D., Petersen, J., Rehermann, B., Shin, E. -C., Thompson, A., van Bommel, F., Wang, F. -S., Watashi, K., Yang, H. -C., Yuan, Z., Yuen, M. -F., Block, T., Miller, V., Protzer, U., Brechot, C., Locarnini, S., Peters, M. G., Schinazi, R. F., Zoulim, F., and Gastroenterology and Hepatology
- Subjects
medicine.medical_specialty ,Hepatitis B virus ,Tuberculosis ,T-Lymphocytes ,[SDV]Life Sciences [q-bio] ,Circular DNA ,Global Health ,Virus Replication ,Antiviral Agents ,Article ,03 medical and health sciences ,0302 clinical medicine ,Hepatitis B, Chronic ,Chronic hepatitis ,medicine ,Global health ,Animals ,Humans ,Disease Eradication ,Intensive care medicine ,Cell Line, Transformed ,B-Lymphocytes ,Immunity, Cellular ,Hepatology ,business.industry ,Public health ,Research ,Liver Neoplasms ,Remission Induction ,Gastroenterology ,virus diseases ,Hepatitis B ,medicine.disease ,digestive system diseases ,3. Good health ,Disease Models, Animal ,030220 oncology & carcinogenesis ,DNA, Viral ,Hepatocytes ,Position paper ,030211 gastroenterology & hepatology ,Immunotherapy ,business ,Malaria ,Forecasting - Abstract
Chronic hepatitis B virus (HBV) infection is a global public health challenge on the same scale as tuberculosis, HIV, and malaria. The International Coalition to Eliminate HBV (ICE-HBV) is a coalition of experts dedicated to accelerating the discovery of a cure for chronic hepatitis B. Following extensive consultation with more than 50 scientists from across the globe, as well as key stakeholders including people affected by HBV, we have identified gaps in our current knowledge and new strategies and tools that are required to achieve HBV cure. We believe that research must focus on the discovery of interventional strategies that will permanently reduce the number of productively infected cells or permanently silence the covalently closed circular DNA in those cells, and that will stimulate HBV-specific host immune responses which mimic spontaneous resolution of HBV infection. There is also a pressing need for the establishment of repositories of standardised HBV reagents and protocols that can be accessed by all HBV researchers throughout the world. The HBV cure research agenda outlined in this position paper will contribute markedly to the goal of eliminating HBV infection worldwide.
- Published
- 2019
26. Laboratory mice born to wild mice have natural microbiota and model human immune responses
- Author
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Jonathan H. Badger, Svetlana Potapova, Nicholas Collins, Seong-Ji Han, Brian G. Vassallo, Benedikt Hild, Samira Tamoutounour, Irina Leonardi, Iliyan D. Iliev, Dimitrios G. Anastasakis, Giorgio Trinchieri, Jasmin Herz, John A. McCulloch, Mark B. St. Claire, Joshua Blatter, Morgan Wall, Matthew S. Dreier, Ashli Hunter, Aishe A. Sarshad, Wuxing Yuan, Shurjo K. Sen, Stephan P. Rosshart, Yasmine Belkaid, Barbara Rehermann, David Wang, and Markus Hafner
- Subjects
Multidisciplinary ,Host Microbial Interactions ,Gastrointestinal Microbiome ,Laboratory mouse ,Immunity ,Animals, Wild ,Biology ,Gut flora ,biology.organism_classification ,Article ,Mice, Inbred C57BL ,Translational Research, Biomedical ,Mice ,Immune system ,Immunology ,Host-Pathogen Interactions ,Models, Animal ,Animals ,Humans ,Human virome ,Microbiome ,Mycobiome - Abstract
INTRODUCTION: Laboratory mice are a mainstay of biomedical research and have been instrumental for many important discoveries in the field of immunology. However, there are also major limitations, including conflicting results rooted in divergent microbiota among research facilities and the limited ability to predict the complex immune responses of humans. Recent studies have shown that conventional laboratory mice are too far removed from natural environmental conditions to faithfully mirror the physiology of free-living mammals like humans. Mammals and their immune systems evolved to survive and thrive in a microbial world and behave differently in a sanitized environment. RATIONALE: To generate a mouse model that more closely resembles the natural mammalian meta-organism with co-evolved microbes and pathogens, we transferred C57BL/6 embryos into wild mice. This resulted in a colony of C57BL/6 mice, which we call “wildlings”. RESULTS: Wildlings resembled wild mice and differed significantly from conventional laboratory mice with regards to their bacterial microbiome at important epithelial barrier sites (gut, skin, and vagina), their gut mycobiome and virome, and their level of pathogen exposure. The natural microbiota of wildlings were stable over multiple generations and resilient against antibiotic, dietary, and microbial challenges. Next, we delineated the immune landscape of wildlings, wild mice, and laboratory mice at immunologically important barrier sites (gut, skin, and vagina), a central non-lymphoid organ (liver), and a central lymphoid organ (spleen) by mass cytometry. Additionally, we characterized the blood immune cell profile by RNA sequencing. The differential contribution of microbial and host genomes in shaping the immune phenotype varied among tissues. Wildlings closely mirrored the wild mouse immune phenotype in the spleen and blood. Finally, we tested the translational research value of wildlings in a retrospective bench-to-bedside approach. This required well-documented, rodent-based studies that had failed upon transitioning to clinical trials in humans. We chose the CD28-superagonist (CD28SA) trial as representative for treatments targeting adaptive immune responses. Although CD28SA expanded anti-inflammatory regulatory T cells (T(regs)) in laboratory mice and showed therapeutic effects in multiple models of autoimmune/inflammatory diseases, the first phase I clinical trial resulted in life-threatening activation of inflammatory T cells and cytokine storms. Similarly, the CD28-superagonist treatment of wildlings, but not laboratory mice, resulted in an inflammatory cytokine response and lack of T(reg) expansion. As representative for trials targeting innate immune responses, we chose anti-TNF-α treatment (anti-TNF-α or TNF-receptor:Fc fusion protein) during septic shock, which was successful in animal models, but failed in humans. Anti-TNF-α treatment during lethal endotoxemia rescued laboratory mice, but not wildlings. Thus, wildlings better phenocopied human immune responses than conventional laboratory mice in the two models studied. CONCLUSION: The wildling model combines resilient natural microbiota and pathogens at all body sites and the tractable genetics of C57BL/6. Given the wide-ranging effects of microbiota on host physiology, natural microbiota-based models may benefit different research fields (e.g. metabolism and neurodegenerative diseases) and may also be applicable to other animals. Such models may enhance the validity and reproducibility of biomedical studies among research institutes, facilitate the discovery of disease mechanisms and treatments that cannot be studied in regular laboratory mice, and increase the translatability of immunological results to humans.
- Published
- 2018
27. Infection trains the host for microbiota-enhanced resistance to pathogens
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Choon Kiat Sim, Vinicius Andrade-Oliveira, Barbara Rehermann, Verena M. Link, Ai Ing Lim, Giorgio Trinchieri, Apollo Stacy, Ji Hoon Oh, P. Juliana Perez-Chaparro, John A. McCulloch, Yasmine Belkaid, Michel Enamorado, Julia A. Segre, and Benedikt Hild
- Subjects
Taurine ,medicine.drug_class ,Cellular respiration ,Colony Count, Microbial ,Colonisation resistance ,Sulfides ,Gut flora ,digestive system ,Article ,General Biochemistry, Genetics and Molecular Biology ,Microbiology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,medicine ,Animals ,Pathogen ,030304 developmental biology ,0303 health sciences ,Bile acid ,biology ,Host (biology) ,Immunity ,Bacterial Infections ,biology.organism_classification ,Gastrointestinal Microbiome ,Mice, Inbred C57BL ,chemistry ,Host-Pathogen Interactions ,030217 neurology & neurosurgery ,Function (biology) - Abstract
The microbiota shields the host against infections in a process known as colonization resistance. How infections themselves shape this fundamental process remains largely unknown. Here, we show that gut microbiota from previously infected hosts display enhanced resistance to infection. This long-term functional remodeling is associated with altered bile acid metabolism leading to the expansion of taxa that utilize the sulfonic acid taurine. Notably, supplying exogenous taurine alone is sufficient to induce this alteration in microbiota function and enhance resistance. Mechanistically, taurine potentiates the microbiota's production of sulfide, an inhibitor of cellular respiration, which is key to host invasion by numerous pathogens. As such, pharmaceutical sequestration of sulfide perturbs the microbiota's composition and promotes pathogen invasion. Together, this work reveals a process by which the host, triggered by infection, can deploy taurine as a nutrient to nourish and train the microbiota, promoting its resistance to subsequent infection.
- Published
- 2021
28. Rapid decrease in hepatitis C viremia by direct acting antivirals improves the natural killer cell response to IFNα
- Author
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Marc G. Ghany, Heiyoung Park, Elenita Rivera, T. Jake Liang, Ashley C. O’Keefe, Elisavet Serti, Barbara Rehermann, and Meghan Keane
- Subjects
Male ,0301 basic medicine ,Pyrrolidines ,Sustained Virologic Response ,Hepacivirus ,Cell Degranulation ,TNF-Related Apoptosis-Inducing Ligand ,chemistry.chemical_compound ,0302 clinical medicine ,Pegylated interferon ,Phosphorylation ,Cells, Cultured ,Sulfonamides ,Imidazoles ,Gastroenterology ,Valine ,Middle Aged ,Viral Load ,Killer Cells, Natural ,STAT1 Transcription Factor ,medicine.anatomical_structure ,Retreatment ,Drug Therapy, Combination ,Female ,030211 gastroenterology & hepatology ,Signal Transduction ,medicine.drug ,Adult ,Daclatasvir ,Viremia ,Antiviral Agents ,Peripheral blood mononuclear cell ,Article ,Natural killer cell ,03 medical and health sciences ,Immune system ,Ribavirin ,medicine ,Humans ,Aged ,business.industry ,Interferon-alpha ,Hepatitis C, Chronic ,Isoquinolines ,medicine.disease ,030104 developmental biology ,chemistry ,Immunology ,Asunaprevir ,Carbamates ,business - Abstract
Objective Chronic HCV infection is characterised by innate immune activation with increased interferon-stimulated genes (ISG) expression and by an altered phenotype of interferon-responsive natural killer (NK) cells. Here, we asked whether a rapid reduction in viremia by daclatasvir (DCV) and asunaprevir (ASV) improves the response to pegylated interferon (PegIFN) in patients who had previously failed a standard course of PegIFN/ribavirin (RBV) therapy. Design Twenty-two HCV-infected non-responders to previous PegIFN/RBV therapy were studied for IFN-responsiveness of NK cells during quadruple (QUAD) therapy with DCV, ASV, PegIFN and RBV. A direct comparison of early NK cell responses in PegIFN/RBV therapy and QUAD therapy was performed for seven patients using paired cryopreserved peripheral blood mononuclear cells (PBMC) from both treatment courses. As a validation cohort, nine DCV/ASV-treated patients were studied for their NK cell response to in vitro stimulation with IFNα. Results The 24 h virological response to QUAD therapy correlated with an increase in signal transducer and activator of transcription 1 (STAT1), phosphorylated STAT1 (pSTAT1) and tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) expression in NK cells, and the STAT1/pSTAT1/TRAIL induction was greater during QUAD therapy than during previous PegIFN/RBV therapy. Successful QUAD therapy as well as successful IFN-free DCV/ASV regimen resulted in an improved functional NK cell response (degranulation and TRAIL expression) to in vitro stimulation with IFNα. Conclusions IFN-responsiveness can be improved by inhibiting HCV replication and reducing the HCV-induced activation of the innate immune response. This may provide a rationale for clinical trials of a brief period of direct acting antiviral therapy followed by PegIFN/RBV therapy to reduce the overall treatment costs in low-income and middle-income countries. Trial registration numbers NCT01888900 and NCT00718172.
- Published
- 2016
29. Systemic toxoplasma infection triggers a long-term defect in the generation and function of naive T lymphocytes
- Author
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David G. Kugler, Dragana Jankovic, Olena Kamenyeva, Diego L. Costa, Stephan P. Rosshart, Alan Sher, Barbara Rehermann, Francis A. Flomerfelt, Karen Laky, Jonathan D. Ashwell, Paul R. Mittelstadt, and Ronald E. Gress
- Subjects
0301 basic medicine ,Senescence ,CD4-Positive T-Lymphocytes ,Immunology ,Thymus Gland ,Biology ,Article ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Immune system ,parasitic diseases ,medicine ,Immunology and Allergy ,Animals ,Pathogen ,Research Articles ,Mice, Knockout ,Mice, Inbred BALB C ,Effector ,Toxoplasma gondii ,T lymphocyte ,biology.organism_classification ,medicine.disease ,Toxoplasmosis ,030104 developmental biology ,Lymphatic system ,Toxoplasma ,030215 immunology - Abstract
Kugler et al. show that systemic infection with Toxoplasma gondii triggers a long-term impairment in thymic function, which leads to an immunodeficient state reflected in decreased antimicrobial resistance., Because antigen-stimulated naive T cells either die as effectors or enter the activated/memory pool, continuous egress of new T lymphocytes from thymus is essential for maintenance of peripheral immune homeostasis. Unexpectedly, we found that systemic infection with the protozoan Toxoplasma gondii triggers not only a transient increase in activated CD4+ Th1 cells but also a persistent decrease in the size of the naive CD4+ T lymphocyte pool. This immune defect is associated with decreased thymic output and parasite-induced destruction of the thymic epithelium, as well as disruption of the overall architecture of that primary lymphoid organ. Importantly, the resulting quantitative and qualitative deficiency in naive CD4+ T cells leads to an immunocompromised state that both promotes chronic toxoplasma infection and leads to decreased resistance to challenge with an unrelated pathogen. These findings reveal that systemic infectious agents, such as T. gondii, can induce long-term immune alterations associated with impaired thymic function. When accumulated during the lifetime of the host, such events, even when occurring at low magnitude, could be a contributing factor in immunological senescence.
- Published
- 2016
30. Tissue-resident T cells in hepatitis B: A new target for cure?
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Fabian J. Bolte and Barbara Rehermann
- Subjects
0301 basic medicine ,Hepatitis B virus ,Functional impairment ,Immunology ,Programmed Cell Death 1 Receptor ,Receptors, Antigen, T-Cell ,Biology ,News ,CD8-Positive T-Lymphocytes ,Insights ,Virus ,Granzymes ,03 medical and health sciences ,0302 clinical medicine ,Hepatitis B, Chronic ,Chronic hepatitis ,Antigens, CD ,Transforming Growth Factor beta ,medicine ,Immunology and Allergy ,Humans ,Antigens ,Cell Proliferation ,Receptors, CXCR6 ,Interleukin-15 ,virus diseases ,Hepatitis B ,medicine.disease ,Virology ,digestive system diseases ,Autocrine Communication ,030104 developmental biology ,Phenotype ,Liver ,030220 oncology & carcinogenesis ,Interleukin-2 ,Receptors, Virus ,Receptors, Chemokine ,Immunologic memory ,Liver pathology ,Immunologic Memory - Abstract
A hallmark of chronic hepatitis B virus (HBV) infection is the functional impairment and depletion of antiviral T cells. In this issue of JEM, Pallett et al. identify a reservoir of functional HBV-specific T cells among liver-resident T cells., A hallmark of chronic hepatitis B virus (HBV) infection is the functional impairment and depletion of antiviral T cells. In this issue of JEM, Pallett et al. (https://doi.org/10.1084/jem.20162115) identify a reservoir of functional HBV-specific T cells among liver-resident T cells.
- Published
- 2017
31. Hepatitis D Virus-Specific CD8
- Author
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Helenie, Kefalakes, Christopher, Koh, John, Sidney, Georgios, Amanakis, Alessandro, Sette, Theo, Heller, and Barbara, Rehermann
- Subjects
Adult ,Male ,Hepatitis B virus ,Herpesvirus 4, Human ,Hepatitis D, Chronic ,viruses ,Programmed Cell Death 1 Receptor ,Cytomegalovirus ,Epitopes, T-Lymphocyte ,CD8-Positive T-Lymphocytes ,Article ,Interleukin-7 Receptor alpha Subunit ,Interferon-gamma ,Young Adult ,Hepatitis B, Chronic ,Humans ,Immunologic Surveillance ,Cells, Cultured ,Hepatitis delta Antigens ,HLA-A Antigens ,virus diseases ,biochemical phenomena, metabolism, and nutrition ,Middle Aged ,Phenotype ,HLA-B Antigens ,Influenza A virus ,Female ,Hepatitis Delta Virus ,Peptides ,Immunologic Memory - Abstract
BACKGROUND & AIM: Hepatitis D virus (HDV) superinfection of patients with chronic HBV infection results in rapid progression to liver cirrhosis. Little is known about HDV-specific T cells and how they contribute to the anti-virus immune response and liver disease pathogenesis. METHODS: We isolated peripheral blood mononuclear cells from 28 patients with chronic HDV and HBV infection, identified HDV-specific CD8(+) T-cell epitopes and characterized HDV-specific CD8(+) T cells. We associated these with HDV sequence variations and clinical features of patients. RESULTS: We identified 6 CD8(+) T-cell epitopes; several were restricted by multiple HLA class I alleles. HDV-specific CD8(+) T cells were as frequent as HBV-specific CD8(+) T cells, but less frequent than T cells with specificity for cytomegalovirus, Epstein-Barr virus, or influenza virus. The ex vivo frequency of activated HDV-specific CD8(+) T cells correlated with transaminase activity. CD8(+) T cell production of interferon gamma following stimulation with HDV peptides correlated inversely with HDV titer. HDV-specific CD8(+) T cells did not express the terminal differentiation marker CD57, and fewer HDV-specific than Epstein-Barr virus-specific CD8(+) T cells were 2B4(+)CD160(+)PD1(+), a characteristic of exhausted cells. About half of the HDV-specific CD8(+) T cells had a memory-like PD1(+)CD127(+)TCF1(hi)T-bet(low) phenotype, which associated with HDV sequence variants with reduced HLA binding and reduced T-cell activation. CONCLUSIONS: CD8(+) T cells isolated from patients with chronic HDV and HBV infection recognize HDV epitopes presented by multiple HLA molecules. The subset of activated DV-specific CD8(+) T cells targets conserved epitopes and likely contributes to disease progression. The subset of memory-like HDV-specific CD8(+) T cells is functional, but unable to clear HDV due to the presence of escape variants.
- Published
- 2018
32. Mucosal-Associated Invariant T Cells in Chronic Inflammatory Liver Disease
- Author
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Fabian J. Bolte and Barbara Rehermann
- Subjects
0301 basic medicine ,Mucosal associated invariant T cell ,Chronic liver disease ,Lymphocyte Activation ,Mucosal-Associated Invariant T Cells ,Article ,Proinflammatory cytokine ,03 medical and health sciences ,Liver disease ,Antigen ,Medicine ,Animals ,Humans ,Hepatitis, Chronic ,Hepatitis ,Gastrointestinal tract ,Antigens, Bacterial ,Hepatology ,business.industry ,Gastrointestinal Microbiome ,medicine.disease ,030104 developmental biology ,Phenotype ,Liver ,Immunology ,Host-Pathogen Interactions ,Cytokines ,Inflammation Mediators ,business - Abstract
The broadening field of microbiome research has led to a substantial reappraisal of the gut–liver axis and its role in chronic liver disease. The liver is a central immunologic organ that is continuously exposed to food and microbial-derived antigens from the gastrointestinal tract. Mucosal-associated invariant T (MAIT) cells are enriched in the human liver and can be activated by inflammatory cytokines and microbial antigens. In chronic inflammatory liver disease, MAIT cells are depleted suggesting an impaired MAIT cell-dependent protection against bacterial infections.
- Published
- 2018
33. Hepatic expression levels of interferons and interferon-stimulated genes in patients with chronic hepatitis C: A phenotype–genotype correlation study
- Author
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Fang Zhang, H Park, Mazen Noureddin, T. J. Liang, Barbara Rehermann, Yaron Rotman, and Emmanuel Thomas
- Subjects
Adult ,Male ,Genotype ,Hepatitis C virus ,Immunology ,Biology ,medicine.disease_cause ,Antiviral Agents ,Polymorphism, Single Nucleotide ,Article ,Correlation ,chemistry.chemical_compound ,Chronic hepatitis ,Interferon ,Ribavirin ,Genetics ,medicine ,Humans ,In patient ,Gene ,Genetics (clinical) ,virus diseases ,Hepatitis C, Chronic ,Middle Aged ,Phenotype ,Liver ,chemistry ,Interferon Regulatory Factors ,Female ,Interferons ,medicine.drug - Abstract
IFNL4 is linked to hepatitis C virus treatment response and type III interferons (IFNs). We studied the functional associations among hepatic expressions of IFNs and IFN-stimulated genes (ISGs), and treatment response to peginterferon and ribavirin. Type I IFNs (IFNA1, IFNB1), type II (IFNG), type III (IFNL1, IFNL2/3), IFNL4 and ISG hepatic expressions were measured by qPCR from in 65 chronic hepatitis C (CHC) patients whose IFNL4-associated rs368234815 and IFNL3-associated rs12989760 genotype were determined. There was a robust correlation of hepatic expression within type I and type III IFNs and between type III IFNs and IFNL4 but no correlation between other IFN types. Expression of ISGs correlated with type III IFNs and IFNL4 but not with type I IFNs. Levels of ISGs and IFNL2/3 mRNAs were lower in IFNL3 rs12979860 CC patients compared with non-CC patients, and in treatment responders, compared with nonresponders. IFNL4-ΔG genotype was associated with high ISG levels and nonresponse. Hepatic levels of ISGs in CHC are associated with IFNL2/3 and IFNL4 expression, suggesting that IFNLs, not other types of IFNs, drive ISG expression. Hepatic IFNL2/3 expression is functionally linked to IFNL4 and IFNL3 polymorphisms, potentially explaining the tight association among ISG expression and treatment response.
- Published
- 2015
34. Immunological aspects of antiviral therapy of chronic hepatitis B virus and hepatitis C virus infections
- Author
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Antonio Bertoletti and Barbara Rehermann
- Subjects
Hepatitis C virus ,medicine.disease_cause ,Antiviral Agents ,Virus ,chemistry.chemical_compound ,New Horizons ,Immune system ,Hepatitis B, Chronic ,medicine ,Humans ,Hepatitis B virus ,Hepatology ,business.industry ,Ribavirin ,virus diseases ,Hepatitis C ,Hepatitis B ,Hepatitis C, Chronic ,medicine.disease ,Acquired immune system ,Virology ,digestive system diseases ,Treatment Outcome ,chemistry ,Immunology ,business - Abstract
Hepatitis B virus (HBV) and hepatitis C virus (HCV) cause a large proportion of acute and chronic liver disease worldwide. Over the past decades many immunological studies defined host immune responses that mediate spontaneous clearance of acute HBV and HCV infection. However, host immune responses are also relevant in the context of treatment-induced clearance of chronic HBV and HCV infection. First, the pretreatment level of interferon-stimulated genes as well as genetic determinants of innate immune responses, such as single nucleotide polymorphisms near the IFNL3 gene, are strong predictors of the response to interferon-alpha (IFN-α)-based therapy. Second, IFN-α, which has been a mainstay of HBV and HCV therapy over decades, and ribavirin, which has also been included in interferon-free direct antiviral therapy for HCV, modulate host immune responses. Third, both IFN-α-based and IFN-α-free treatment regimens of HBV and HCV infection alter the short-term and long-term adaptive immune response against these viruses. Finally, treatment studies have not just improved the clinical outcomes, but also provided opportunities to study virus-host interaction. This review summarizes our current knowledge on how a patient's immune response affects the treatment outcome of HBV and HCV infection and how innate and adaptive immune responses themselves are altered by the different treatment regimens.
- Published
- 2015
35. Durability of Antibody Response Against Hepatitis B Virus in Healthcare Workers Vaccinated as Adults
- Author
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Jay H. Hoofnagle, Marc G. Ghany, Xiongce Zhao, Elenita Rivera, Naveen Gara, JM Werner, Barbara Rehermann, T. Jake Liang, and Adil A. Abdalla
- Subjects
Adult ,Male ,Microbiology (medical) ,HBsAg ,Time Factors ,Hepatitis B vaccine ,Adolescent ,Health Personnel ,Population ,Hepatitis A vaccine ,Immunization, Secondary ,Booster dose ,medicine.disease_cause ,complex mixtures ,Young Adult ,Humans ,Medicine ,Hepatitis B Vaccines ,Serologic Tests ,Vaccines, Combined ,Hepatitis B Antibodies ,education ,Articles and Commentaries ,Hepatitis B virus ,Hepatitis A Vaccines ,education.field_of_study ,Hepatitis B Surface Antigens ,Maryland ,business.industry ,Vaccination ,Middle Aged ,Hepatitis B ,medicine.disease ,Hepatitis B Core Antigens ,Logistic Models ,Infectious Diseases ,Immunology ,Regression Analysis ,Female ,business ,Immunologic Memory ,Follow-Up Studies - Abstract
The implementation of vaccination programs worldwide against hepatitis B virus (HBV) has reduced the morbidity and mortality of acute and chronic HBV infection and the incidence of hepatocellular carcinoma, particularly in endemic regions [1–3]. Vaccination against HBV consists of 3 or 4 intramuscular injections of recombinant hepatitis B surface antigen (HBsAg) at varying schedules [4]. Response rates to primary vaccination are high, with 85%–100% of vaccinees developing antibody to HBsAg (anti-HBs) ≥10 mIU/mL [5], a level that is considered protective [5–9]. Factors found to be associated with nonresponse include male sex, increasing age at vaccination (>40 years old), obesity, alcoholism, smoking, and genetic factors [10–12]. Asymptomatic breakthrough infections (detected by the presence of antibody to hepatitis B core antigen [anti-HBc] or HBV DNA in serum) have been reported in vaccinated persons with a documented initial antibody response [13, 14]. Long-term follow-up studies of persons who were vaccinated as infants have reported absence of anti-HBs in 50%–70% of persons 15–30 years later [13, 15–18]. In contrast, data on the longevity of immunity afforded by hepatitis B vaccine in a healthy adult population are scarce. The few available studies in young adults who initially responded to a past primary vaccine series with antibody concentrations of ≥10 mIU/mL reported that 17%–50% have low or undetectable anti-HBs (reflecting anti-HBs loss) 10–15 years after vaccination [14, 19]. Whether low or undetectable levels of anti-HBs predispose to subsequent infection is unknown. Moreover, whether individuals may respond to a hepatitis B vaccine booster to maintain long-term protection is unknown. Current guidelines do not recommend booster doses, but the duration of long-term protection is unknown [4, 20]. Healthcare workers (HCWs) in the United States are mandated to receive hepatitis B vaccine and are at risk for hepatitis B through occupational exposure. Therefore, they would be an ideal population to assess durability of antibody response and long-term (≥10 years) vaccine protection and to determine response to a booster dose in those who did not maintain the immune response to primary vaccination as adults.
- Published
- 2014
36. Advances in hepatitis C research and treatment
- Author
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Barbara Rehermann
- Subjects
Hepatology ,biology ,business.industry ,Treatment regimen ,Hepatitis C virus ,Gastroenterology ,HCV genotypes ,virus diseases ,Context (language use) ,Lipid metabolism ,Hepatitis C ,medicine.disease ,medicine.disease_cause ,Virology ,digestive system diseases ,Intracellular membrane ,03 medical and health sciences ,0302 clinical medicine ,Immunology ,biology.protein ,medicine ,030211 gastroenterology & hepatology ,030212 general & internal medicine ,business ,Polymerase - Abstract
In 2015, new treatment regimens were revealed that achieve >95% cure rates for all HCV genotypes. The HCV polymerase structure was solved in catalytically relevant HCV replication steps and in the context of nucleotide analogue inhibition. Moreover, HCV research taught us new links between innate antiviral responses, lipid metabolism and intracellular membrane formation.
- Published
- 2016
37. Ribavirin improves the IFN-γ response of natural killer cells to IFN-based therapy of hepatitis C virus infection
- Author
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Yaron Rotman, Elisavet Serti, Jordan J. Feld, JM Werner, Golo Ahlenstiel, T. Jake Liang, Jonathan D. Stoltzfus, Xenia Chepa-Lotrea, Mazen Noureddin, and Barbara Rehermann
- Subjects
Hepatology ,Ribavirin ,Hepatitis C virus ,Alpha interferon ,Biology ,medicine.disease_cause ,chemistry.chemical_compound ,Interleukin 21 ,chemistry ,Interferon ,Immunology ,Interleukin 12 ,medicine ,Cytotoxic T cell ,Interferon gamma ,medicine.drug - Abstract
Ribavirin (RBV) is an important component of interferon (IFN)-based and direct antiviral treatment regimens for hepatitis C virus (HCV) infection. Immunomodulation, in particular improvement of the host IFN response, has been proposed as RBV's mechanism of action. Natural killer (NK) cells are sensitive biomarkers for IFN-α/β receptor signaling, as NK cell cytotoxicity and IFN-γ production are regulated by signal transducer and activator of transcription (STAT)1- and STAT4-phosphorylation, respectively. Specifically, pSTAT1-dependent NK cell cytotoxicity increases and pSTAT4-dependent IFN-γ production decreases in response to endogenous, virus-induced IFN-α and during IFN-α-based therapy. To assess whether RBV has a direct effect on NK cells and/or improves the IFN-γ response of NK cells in the presence of IFN-α, we prospectively studied 22 HCV patients with and 32 patients without 4 weeks of RBV pretreatment, who all received subsequent pegylated (Peg)IFN/ribavirin combination therapy. During RBV pretreatment, both the frequency of CD56dim NK cells with cytotoxic effector functions and the frequency of CD56bright NK cells with the capacity to produce IFN-γ decreased (P = 0.049 and P = 0.001, respectively). In vitro or in vivo exposure of NK cells to RBV improved the pSTAT4 (P
- Published
- 2014
38. Hepatitis D Virus-Specific CD8+ T Cells Have a Memory-Like Phenotype Associated With Viral Immune Escape in Patients With Chronic Hepatitis D Virus Infection
- Author
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Alessandro Sette, Georgios Amanakis, Helenie Kefalakes, Christopher Koh, John Sidney, Theo Heller, and Barbara Rehermann
- Subjects
0301 basic medicine ,Hepatitis B virus ,Hepatology ,viruses ,Gastroenterology ,virus diseases ,Human leukocyte antigen ,biochemical phenomena, metabolism, and nutrition ,Biology ,medicine.disease_cause ,Virology ,Epitope ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Immune system ,Interferon ,medicine ,Cytotoxic T cell ,030211 gastroenterology & hepatology ,Hepatitis D virus ,CD8 ,medicine.drug - Abstract
Background & Aim Hepatitis D virus (HDV) superinfection of patients with chronic HBV infection results in rapid progression to liver cirrhosis. Little is known about HDV-specific T cells and how they contribute to the antiviral immune response and liver disease pathogenesis. Methods We isolated peripheral blood mononuclear cells from 28 patients with chronic HDV and HBV infection, identified HDV-specific CD8+ T-cell epitopes, and characterized HDV-specific CD8+ T cells. We associated these with HDV sequence variations and clinical features of patients. Results We identified 6 CD8+ T-cell epitopes; several were restricted by multiple HLA class I alleles. HDV-specific CD8+ T cells were as frequent as HBV-specific CD8+ T cells but were less frequent than T cells with specificity for cytomegalovirus, Epstein–Barr virus, or influenza virus. The ex vivo frequency of activated HDV-specific CD8+ T cells correlated with transaminase activity. CD8+ T-cell production of interferon gamma after stimulation with HDV peptides correlated inversely with HDV titer. HDV-specific CD8+ T cells did not express the terminal differentiation marker CD57, and fewer HDV-specific than Epstein–Barr virus–specific CD8+ T cells were 2B4+CD160+PD1+, a characteristic of exhausted cells. Approximately half of the HDV-specific CD8+ T cells had a memory-like PD1+CD127+TCF1hiT-betlow phenotype, which associated with HDV sequence variants with reduced HLA binding and reduced T-cell activation. Conclusions CD8+ T cells isolated from patients with chronic HDV and HBV infection recognize HDV epitopes presented by multiple HLA molecules. The subset of activated HDV-specific CD8+ T cells targets conserved epitopes and likely contributes to disease progression. The subset of memory-like HDV-specific CD8+ T cells is functional but unable to clear HDV because of the presence of escape variants. ClinicalTrials.gov , Numbers: NCT02511431 , NCT00023322 , NCT01495585 , and NCT00001971 . GenBank accession, Number: MK333199-333226
- Published
- 2019
39. Sequence Analysis of Hepatitis C Virus From Patients With Relapse After a Sustained Virological Response: Relapse or Reinfection?
- Author
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Jay H. Hoofnagle, Maria M. Rivera, Pothu Raju Nagabhyru, Mary DeMino, Sandra Page, T. Jake Liang, Christopher Koh, Koji Hara, Theo Heller, and Barbara Rehermann
- Subjects
Adult ,Male ,Cirrhosis ,Genotype ,Hepatitis C virus ,medicine.medical_treatment ,Hepacivirus ,Liver transplantation ,medicine.disease_cause ,Antiviral Agents ,Major Articles and Brief Reports ,Liver disease ,chemistry.chemical_compound ,Recurrence ,Pegylated interferon ,medicine ,Humans ,Immunology and Allergy ,Phylogeny ,medicine.diagnostic_test ,business.industry ,Ribavirin ,virus diseases ,Middle Aged ,Hepatitis C, Chronic ,medicine.disease ,digestive system diseases ,Infectious Diseases ,Liver ,chemistry ,Liver biopsy ,Hepatocellular carcinoma ,Immunology ,RNA, Viral ,Female ,business ,Sequence Alignment ,medicine.drug - Abstract
(See the editorial commentary by Tillmann on pages 6–8.) Hepatitis C virus (HCV) infection affects 180 million persons worldwide and at least 3.2 million in the United States [1, 2]. It is one of the main causes of progressive liver diseases, such as cirrhosis and hepatocellular carcinoma, and the leading indication for liver transplantation [3]. Combination therapy of pegylated interferon and ribavirin is successful in approximately 50% of infected patients, resulting in clearance of HCV RNA from serum, which is accompanied by normalization of liver biochemical test results and improvement of liver histologic findings [4, 5]. A sustained virological response (SVR) is defined as the absence of detectable HCV RNA as measured by a sensitive reverse-transcription polymerase chain reaction (RT-PCR) at least 24 weeks after termination of treatment [4]. The majority of patients who have a SVR have resolution of their liver disease biochemically and histologically. These characteristics have led to the acceptance of a SVR as an appropriate end point of antiviral therapy for chronic hepatitis C. Several groups have examined the durability of a SVR in patients with chronic hepatitis C after treatment [6–10]. SVR is maintained in almost all patients and is associated with long-term good prognosis. However, long-term follow up has indicated that relapse of infection, defined as detection of HCV RNA in serum, can occur, although at a rates of 24 weeks after stopping therapy) occurred in 4.2% [12]. These findings raise the issue of whether a sustained response to therapy results in permanent eradication of the virus and cure of the infection, as opposed to long-term suppression of viral replication maintained by immunological factors. There are few data in the literature regarding the relapse of HCV infection in patients with resolved infection. Most reports are anecdotal and have not rigorously explored the nature of the virus in individuals with apparent reinfection. It is unclear whether these patients have true relapse and are persistently infected with the same HCV strain as before treatment or whether they have been reinfected with a completely novel HCV strain. To address this question, we analyzed HCV RNA sequences in specimens from 3 patients in whom HCV RNA was redetected in serum (by commercial assays) after they had achieved a SVR, and we compared the RNA sequences of HCV recovered during late relapse with those of HCV recovered from serum before treatment. In this article, these patients are referred to as “patients with late relapse” because HCV infection reappeared >6 months after termination of therapy and because it was unknown whether they had relapse or reinfection. Additionally, RNA was extracted from liver biopsy specimens obtained from these patients at the time they achieved a SVR to determine whether the liver was a reservoir for HCV in patients with a SVR.
- Published
- 2013
40. Innate immune responses in hepatitis C virus-exposed healthcare workers who do not develop acute infection
- Author
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Averell H. Sherker, Theo Heller, M'Lou Stevens, Ellen R. Kessler, Kathleen S. Bean, James M. Schmitt, JM Werner, Barbara Rehermann, Ann Marie Gordon, and Arlene Sheets
- Subjects
Adult ,Male ,Chemokine ,Health Personnel ,T cell ,Hepatitis C virus ,Adaptive Immunity ,Biology ,medicine.disease_cause ,Article ,TNF-Related Apoptosis-Inducing Ligand ,Immune system ,Immunity ,Occupational Exposure ,medicine ,Humans ,Prospective Studies ,Viremia ,Aged ,Chemokine CCL3 ,Innate immune system ,Hepatology ,virus diseases ,Middle Aged ,Natural killer T cell ,Acquired immune system ,Hepatitis C ,Virology ,Immunity, Innate ,digestive system diseases ,Interleukin-2 Receptor beta Subunit ,medicine.anatomical_structure ,Acute Disease ,Immunology ,biology.protein ,Natural Killer T-Cells ,Female - Abstract
Hepatitis C virus (HCV) infection typically results in chronic disease with HCV outpacing antiviral immune responses. Here we asked whether innate immune responses are induced in healthcare workers who are exposed to small amounts of HCV, but do not develop systemic infection and acute liver disease. Twelve healthcare workers with accidental percutaneous exposure to HCV-infected blood were prospectively studied up to 6 months for phenotype and function of NKT and NK cells, kinetics of serum chemokines, and vigor and specificity of HCV-specific T cell responses. Eleven healthcare workers tested negative for HCV RNA and HCV-antibodies. All but one of these aviremic cases displayed NKT cell activation, increased serum chemokines levels, and NK cell responses with increased CD122, NKp44, NKp46 and NKG2A expression, cytotoxicity (as determined by TRAIL and CD107a expression) and IFN-γ production. This multifunctional NK cell response appeared a month earlier than in the one health care worker who developed high-level viremia, and it differed from the impaired IFN-γ production, which is typical for NK cells in chronic HCV infection. The magnitude of NKT cell activation and NK cell cytotoxicity correlated with the magnitude of the subsequent HCV-specific T cell response. T cell responses targeted nonstructural HCV sequences that require translation of viral RNA, which suggests that transient or locally contained HCV replication occurred without detectable systemic viremia. Collectively, these results demonstrate that exposure to small amounts of HCV induces innate immune responses, which correlate with the subsequent HCV-specific T cell response and may contribute to antiviral immunity.
- Published
- 2013
41. The Frequency of CD127 + Hepatitis C Virus (HCV)-Specific T Cells but Not the Expression of Exhaustion Markers Predicts the Outcome of Acute HCV Infection
- Author
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Eui-Cheol Shin, Michelina Nascimbeni, Laura Caggiari, Stephen M. Feinstone, Valli De Re, Marian E. Major, Su-Hyung Park, Charles M. Rice, and Barbara Rehermann
- Subjects
Pan troglodytes ,Hepatitis C virus ,Hepacivirus ,Immunology ,Acute infection ,medicine.disease_cause ,Microbiology ,Virus ,Interleukin-7 Receptor alpha Subunit ,T-Lymphocyte Subsets ,Virology ,medicine ,Animals ,Interleukin-7 receptor ,biology ,Primate Diseases ,virus diseases ,Hepatitis C ,medicine.disease ,biology.organism_classification ,Phenotype ,Blockade ,Insect Science ,Pathogenesis and Immunity - Abstract
T cells are exhausted and overexpress inhibitory molecules in chronic hepatitis C virus (HCV) infection. It is unclear whether this is the cause or consequence of HCV persistence. By studying serial blood and liver samples of chimpanzees during acute infection, we demonstrate that the early expression of the memory precursor marker CD127 on HCV-specific T cells, but not the expression of inhibitory molecules on those T cells or their ligands in the liver, predicts the outcome of acute infection.
- Published
- 2013
42. A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus
- Author
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Jacquie Astemborski, Nathan Brand, Ruth M. Pfeiffer, Faruk Sheikh, Barbara Rehermann, Sabrina Chen, Harold Dickensheets, Luyang Liu, Charles D. Howell, Brian Muchmore, Dianna Hergott, Herbert L. Bonkovsky, Ludmila Prokunina-Olsson, Raymond P. Donnelly, McAnthony Tarway, Wei Tang, Brian R. Edlin, Heiyoung Park, David L. Thomas, Adam Mumy, Thomas R. O'Brien, Indu Kohaar, Timothy R. Morgan, and Patricia Porter-Gill
- Subjects
Genetic Markers ,Hepatitis C virus ,medicine.disease_cause ,Models, Biological ,Linkage Disequilibrium ,Statistics, Nonparametric ,Frameshift mutation ,Species Specificity ,Interferon ,Genetics ,medicine ,Humans ,Phosphorylation ,STAT2 ,Gene ,Microscopy, Confocal ,Polymorphism, Genetic ,biology ,Sequence Analysis, RNA ,Gene Expression Profiling ,Interleukins ,Antibodies, Monoclonal ,RNA ,STAT2 Transcription Factor ,Hep G2 Cells ,Hepatitis C ,medicine.disease ,Virology ,STAT1 Transcription Factor ,Genetic marker ,biology.protein ,Chromosomes, Human, Pair 19 ,medicine.drug - Abstract
Chronic infection with hepatitis C virus (HCV) is a common cause of liver cirrhosis and cancer. We performed RNA sequencing in primary human hepatocytes activated with synthetic double-stranded RNA to mimic HCV infection. Upstream of IFNL3 (IL28B) on chromosome 19q13.13, we discovered a new transiently induced region that harbors a dinucleotide variant ss469415590 (TT or ΔG), which is in high linkage disequilibrium with rs12979860, a genetic marker strongly associated with HCV clearance. ss469415590[ΔG] is a frameshift variant that creates a novel gene, designated IFNL4, encoding the interferon-λ4 protein (IFNL4), which is moderately similar to IFNL3. Compared to rs12979860, ss469415590 is more strongly associated with HCV clearance in individuals of African ancestry, although it provides comparable information in Europeans and Asians. Transient overexpression of IFNL4 in a hepatoma cell line induced STAT1 and STAT2 phosphorylation and the expression of interferon-stimulated genes. Our findings provide new insights into the genetic regulation of HCV clearance and its clinical management.
- Published
- 2013
43. HCV in 2015: Advances in hepatitis C research and treatment
- Author
-
Barbara, Rehermann
- Subjects
Research ,Humans ,Hepatitis C - Abstract
In 2015, new treatment regimens were revealed that achieve95% cure rates for all HCV genotypes. The HCV polymerase structure was solved in catalytically relevant HCV replication steps and in the context of nucleotide analogue inhibition. Moreover, HCV research taught us new links between innate antiviral responses, lipid metabolism and intracellular membrane formation.
- Published
- 2016
44. R2d2 drives selfish sweeps in the house mouse
- Author
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David W. Threadgill, Wesley J. Jolley, Maria da Graça Ramalhinho, James Holt, Amanda J. Chunco, Lydia Ortiz de Solorzano, Daniel W. Förster, Daniel Pomp, Andrew Holmes, Fernando Pardo-Manuel de Villena, Sofia A. Grize, Leonard McMillan, Sofia I. Gabriel, Mabel D. Giménez, John P. Didion, Jeremy S. Herman, Jeremy B. Searle, George M. Weinstock, Riccardo Castiglia, İslam Gündüz, Kunjie Hua, Timothy A. Bell, Karl J. Campbell, John E. French, Janice Britton-Davidian, Karen L. Svenson, Andrew P. Morgan, Elissa J. Chesler, Carol J. Bult, Maria da Luz Mathias, Daniel M. Gatti, George P. Mitsainas, James J. Crowley, Rachel C. McMullan, Pat Thomas-Laemont, Heidi C. Hauffe, Yung-Hao Ching, Meng Shin Shiao, Stephan P. Rosshart, Liran Yadgary, María José López-Fuster, Emanuela Solano, Barbara Rehermann, Gary A. Churchill, Jacint Ventura Queija, Eva B. Giagia-Athanasopoulou, Theodore Garland, Anna K. Lindholm, University of Zurich, de Villena, Fernando Pardo-Manuel, Lineberger Comprehensive Cancer Center (UNC Lineberger), University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), Carolina Center for Genome Sciences, Institut des Sciences de l'Evolution de Montpellier (UMR ISEM), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Montpellier (UM)-Institut de recherche pour le développement [IRD] : UR226-Centre National de la Recherche Scientifique (CNRS), The Jackson Laboratory [Bar Harbor] (JAX), Island Conservation, University of Queensland [Brisbane], Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Elon University [NC, USA], University of North Carolina System (UNC), Leibniz Institute for Zoo and Wildlife Research (IZW), Leibniz Association, National Institute of Environmental Health Sciences [Durham] (NIEHS-NIH), National Institutes of Health [Bethesda] (NIH), Centre for Environmental and Marine Studies [Aveiro] (CESAM), Universidade de Aveiro, Universidade de Lisboa = University of Lisbon (ULISBOA), University of California [Riverside] (UC Riverside), University of California (UC), Department of Biology [Patras], University of Patras, Consejo Nacional de Investigaciones Científicas y Técnicas [Buenos Aires] (CONICET), Universidad Nacional de Misiones, Universität Zürich [Zürich] = University of Zurich (UZH), Ondokuz Mayis University (OMU), National Institute on Alcohol Abuse and Alcoholism (NIAAA), Fondazione Edmund Mach - Edmund Mach Foundation [Italie] (FEM), Department of Computer Science [Chapel Hill], Universitat de Barcelona (UB), National Institute of Diabetes and Digestive and Kidney Diseases [Bethesda], Department of Ecology and Evolutionary Biology [Ithaca], Cornell University [New York], Mahidol University [Bangkok], Texas A&M University [College Station], Universitat Autònoma de Barcelona (UAB), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École pratique des hautes études (EPHE), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Universidade de Lisboa (ULISBOA), University of California [Riverside] (UCR), University of California, University of Patras [Patras], Ondokuz Mayis University, and OMÜ
- Subjects
Male ,0301 basic medicine ,MESH: Selection, Genetic ,Meiotic Drive ,House Mouse ,purl.org/becyt/ford/1 [https] ,Mice ,Settore BIO/05 - ZOOLOGIA ,0302 clinical medicine ,Darwinian Fitness ,MUS MUSCULUS DOMESTICUS ,MESH: Animals ,MESH: Genetic Variation ,MESH: Models, Genetic ,Selective sweep ,MESH: Evolution, Molecular ,2. Zero hunger ,Genetics ,Selfish Genes ,education.field_of_study ,Nuclear Proteins ,RNA-Binding Proteins ,Meiotic drive ,Adaptation, Physiological ,Biological Evolution ,Fixation (population genetics) ,Fast Track ,590 Animals (Zoology) ,Female ,MESH: DNA Copy Number Variations ,CIENCIAS NATURALES Y EXACTAS ,Selective Sweep ,Selfish genes ,MESH: Mutation ,DNA Copy Number Variations ,Otras Ciencias Biológicas ,Population ,MESH: Genetics, Population ,MESH: Biological Evolution ,Biology ,R2d2 ,Evolution, Molecular ,Ciencias Biológicas ,03 medical and health sciences ,10127 Institute of Evolutionary Biology and Environmental Studies ,Genetic drift ,1311 Genetics ,Genetic variation ,1312 Molecular Biology ,Animals ,Selection, Genetic ,purl.org/becyt/ford/1.6 [https] ,education ,Molecular Biology ,MESH: Mice ,Alleles ,Ecology, Evolution, Behavior and Systematics ,Repetitive Sequences, Nucleic Acid ,MESH: Repetitive Sequences, Nucleic Acid ,[SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE] ,Models, Genetic ,MESH: Alleles ,Genetic Variation ,MESH: Adaptation, Physiological ,MESH: Male ,House mouse ,[SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics ,Genetics, Population ,030104 developmental biology ,MESH: RNA-Binding Proteins ,1105 Ecology, Evolution, Behavior and Systematics ,Mutation ,570 Life sciences ,biology ,MESH: Nuclear Proteins ,MESH: Female ,030217 neurology & neurosurgery - Abstract
Mitsainas, George/0000-0003-4976-8275; Lindholm, Anna K/0000-0001-8460-9769; Mathias, Maria da Luz/0000-0003-3876-958X; Foerster, Daniel/0000-0002-6934-0404; Hauffe, Heidi Christine C/0000-0003-3098-8964; Threadgill, David W/0000-0003-3538-1635; Gabriel, Sofia I/0000-0003-3702-4631; Chesler, Elissa/0000-0002-5642-5062; Didion, John/0000-0002-8111-6261; solano, emanuela/0000-0001-8482-9243; Weinstock, George/0000-0002-2997-4592; McMullan, Rachel/0000-0003-0297-4549; Holt, James/0000-0001-6411-9236; Rehermann, Barbara/0000-0001-6832-9951 WOS: 000376170300001 PubMed: 26882987 A selective sweep is the result of strong positive selection driving newly occurring or standing genetic variants to fixation, and can dramatically alter the pattern and distribution of allelic diversity in a population. Population-level sequencing data have enabled discoveries of selective sweeps associated with genes involved in recent adaptations in many species. In contrast, much debate but little evidence addresses whether "selfish" genes are capable of fixation-thereby leaving signatures identical to classical selective sweeps-despite being neutral or deleterious to organismal fitness. We previously described R2d2, a large copy-number variant that causes nonrandom segregation of mouse Chromosome 2 in females due to meiotic drive. Here we show population-genetic data consistent with a selfish sweep driven by alleles of R2d2 with high copy number (R2d2(HC)) in natural populations. We replicate this finding inmultiple closed breeding populations from six outbred backgrounds segregating for R2d2 alleles. We find that R2d2(HC) rapidly increases in frequency, and in most cases becomes fixed in significantly fewer generations than can be explained by genetic drift. R2d2(HC) is also associated with significantly reduced litter sizes in heterozygous mothers, making it a true selfish allele. Our data provide direct evidence of populations actively undergoing selfish sweeps, and demonstrate that meiotic drive can rapidly alter the genomic landscape in favor of mutations with neutral or even negative effects on overall Darwinian fitness. Further study will reveal the incidence of selfish sweeps, and will elucidate the relative contributions of selfish genes, adaptation and genetic drift to evolution. National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [T32GM067553, F30MH103925, P50GM076468, K01MH094406, DK-076050, DK-056350, AG038070]; National Science FoundationNational Science Foundation (NSF) [IOS-1121273]; Vaadia-BARD Postdoctoral Fellowship AwardUS-Israel Binational Science Foundation [FI-478-13]; U.S. Army Medical Research and Materiel CommandU.S. Army Medical Research & Materiel Command (USAMRMC) [W81XWH-11-1-0762]; Jackson Laboratory new investigator funds; National Center for Scientific Research, France [ISEM 2016-002]; University of Rome "La Sapienza"; Claraz-Stiftung; Natural Environment Research Council (UK)NERC Natural Environment Research Council; EU Human Capital and Mobility Programme [CHRX-CT93-0192]; Foundation for Science and Technology, PortugalPortuguese Foundation for Science and Technology [PTDC/BIA-EVF/116884/2010, UID/AMB/50017/2013]; Spanish "Ministerio de Ciencia y Tecnologia"Spanish Government [CGL2007-62111]; "Ministerio de Economia y Competitividad"Spanish Government [CGL2010-15243]; School of Medicine at University of North Carolina We wish to thank all the scientists and research personnel who collected and processed the samples used in this study. In particular we acknowledge Luanne Peters and Alex Hong-Tsen Yu for providing critical samples; Ryan Buus and T. Justin Gooch for isolating DNA for high-density genotyping of wild-caught mice; and Vicki Cappa, A. Cerveira, Guila Ganem, Ron and Annabelle Lesher, K. Said, Toni Schelts, Dan Small, and J. Tapisso for aiding in mouse trapping. We thank Muriel Davisson at the Jackson Laboratory for maintaining, for several decades, tissue samples from breeding colonies used to generate wild-derived inbred strains. We also thank Francis Collins, Jim Evans, Matthew Hahn, and Corbin Jones for comments on an earlier version of this manuscript. This work was supported by the National Institutes of Health T32GM067553 to J.P.D. and A.P.M., F30MH103925 to A.P.M., P50GM076468 to E.J.C., G.A.C., and F.P.M.V., K01MH094406 to J.J.C., DK-076050 and DK-056350 to D.P., AG038070 to G.A.C, and the intramural research program to B.R. and S.P.R.; National Science Foundation IOS-1121273 to T.G.; Vaadia-BARD Postdoctoral Fellowship Award FI-478-13 to L.Y.; U.S. Army Medical Research and Materiel Command W81XWH-11-1-0762 to C.J.B.; The Jackson Laboratory new investigator funds to E.J.C.; The National Center for Scientific Research, France to J.B.D. (this is contribution no ISEM 2016-002); the University of Rome "La Sapienza" to R.C. and E.S.; Claraz-Stiftung to S.G. and A.L.; Natural Environment Research Council (UK) to M.D.G., H.C.H., and J.B.S.; EU Human Capital and Mobility Programme (CHRX-CT93-0192) to H.C.H. and J.B.S.; Foundation for Science and Technology, Portugal PTDC/BIA-EVF/116884/2010 and UID/AMB/50017/2013 to S.I.G., M.L.M., and J.B.S.; Spanish "Ministerio de Ciencia y Tecnologia" CGL2007-62111 and "Ministerio de Economia y Competitividad" CGL2010-15243 to J.V.;and the Oliver Smithies Investigator funds provided by the School of Medicine at University of North Carolina to F.P.M.V. All data are made available at http://csbio.unc.edu/r2d2/. The authors declare no competing financial interests. Correspondence and requests for materials should be addressed to F.P.M.V. (fernando@med.unc.edu).
- Published
- 2016
45. The clinical relevance of persistent recombinant immunoblot assay-indeterminate reactions: insights into the natural history of hepatitis C virus infection and implications for donor counseling
- Author
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Peter D. Burbelo, Addisalem T. Makuria, Joan Gibble, Robert D. Allison, Barbara Rehermann, Sukanya Raghuraman, Harvey J. Alter, and Cathy Cantilena
- Subjects
biology ,business.industry ,Hepatitis C virus ,Hepacivirus ,Immunology ,Context (language use) ,Hematology ,Hepatitis C ,medicine.disease_cause ,medicine.disease ,biology.organism_classification ,Virus ,Serology ,Antigen ,medicine ,biology.protein ,Immunology and Allergy ,Antibody ,business - Abstract
BACKGROUND: Recombinant immunoblot assay (RIBA) is used to determine the specificity of antibody to hepatitis C virus (anti-HCV). The RIBA result is recorded as positive, negative, or indeterminate. The interpretation and significance of RIBA-indeterminate reactions are unclear. We addressed the clinical relevance of these reactions in the context of the natural history of HCV infection in a prospectively followed cohort of anti-HCV–positive blood donors. STUDY DESIGN AND METHODS: Donor demographics, exposure history, and humoral and cell-mediated immunity (CMI) were compared in 15 RIBA-indeterminate subjects, nine chronic HCV carriers, and eight spontaneously recovered subjects. Serum samples were tested for anti-HCV by a quantitative, liquid luciferase immunoprecipitation system (LIPS). CMI was assessed by interferon-γ enzyme-linked immunosorbent spot assay. RESULTS: In the LIPS assay, the sum of antibody responses to six HCV antigens showed significant (p
- Published
- 2012
46. The natural history of acute hepatitis C: clinical presentation, laboratory findings and treatment outcomes
- Author
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Yoon J. Park, Rohit Loomba, R. McBurney, Barbara Rehermann, Steven K. Herrine, Maria M. Rivera, Jay H. Hoofnagle, Harvey J. Alter, V. Haynes-Williams, Theo Heller, and T. J. Liang
- Subjects
medicine.medical_specialty ,Hepatology ,business.industry ,Ribavirin ,Hepatitis C virus ,Gastroenterology ,virus diseases ,Jaundice ,medicine.disease_cause ,Natural history ,chemistry.chemical_compound ,Chronic infection ,Pharmacotherapy ,chemistry ,Interferon ,Internal medicine ,Immunology ,Severity of illness ,medicine ,Pharmacology (medical) ,medicine.symptom ,business ,medicine.drug - Abstract
Aliment Pharmacol Ther 2011; 33: 559–565 Summary Background Acute hepatitis C has variable modes of presentation and frequently results in chronic infection. Its optimal management has yet to be defined. Aim To establish natural history and complications of treatment of acute hepatitis C. Methods Data from all patients presenting with acute hepatitis C to the National Institutes of Health between 1994 and 2007 were reviewed. Results Twenty-five patients were identified. Symptoms were reported by 80% and jaundice by 40%. Aminotransferase levels and hepatitis C virus (HCV) RNA levels fluctuated greatly; 18% of patients were intermittently negative for HCV RNA. Five patients recovered spontaneously whereas 20 developed chronicity or received interferon-based therapy during the acute phase. Among 15 patients treated during the acute phase with peginterferon with or without ribavirin for 24 weeks, all became HCV RNA negative within 4–8 weeks, and all except two (HIV-positive) achieved a sustained virological response. Side effects (particularly psychiatric) were common and limited treatment in 30%. Conclusions Among 25 patients with acute HCV infection, fluctuating illness was common and spontaneous recovery occurred in only 20%. Anti-viral treatment with a 24-week course of peginterferon and ribavirin was highly effective, but marked by frequent and severe side effects.
- Published
- 2010
47. Non-classical Immunity Controls Microbiota Impact on Skin Immunity and Tissue Repair
- Author
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Ivan Vujkovic-Cvijin, Nicholas Collins, Thomas M. Kristie, Barbara Rehermann, Samira Tamoutounour, Seong-Ji Han, Alejandro V. Villarino, Jesse H. Arbuckle, Chyung Ru Wang, Jahangheer S. Shaik, Shurjo K. Sen, Jonathan L. Linehan, Yasmine Belkaid, Margery G. Smelkinson, John J. O'Shea, Jason M. Brenchley, Giorgio Trinchieri, Amiran Dzutsev, Allyson L. Byrd, Nicolas Bouladoux, Oliver J. Harrison, and Stephan P. Rosshart
- Subjects
0301 basic medicine ,T-Lymphocytes ,Transgene ,Mice, Transgenic ,Inflammation ,CD8-Positive T-Lymphocytes ,Adaptive Immunity ,Biology ,Article ,General Biochemistry, Genetics and Molecular Biology ,Mice ,03 medical and health sciences ,Immune system ,Immunity ,MHC class I ,Staphylococcus epidermidis ,medicine ,Animals ,Skin immunity ,Symbiosis ,Skin ,Bacteria ,Effector ,Microbiota ,Histocompatibility Antigens Class I ,Acquired immune system ,Cell biology ,030104 developmental biology ,Gene Expression Regulation ,biology.protein ,medicine.symptom - Abstract
Summary Mammalian barrier surfaces are constitutively colonized by numerous microorganisms. We explored how the microbiota was sensed by the immune system and the defining properties of such responses. Here, we show that a skin commensal can induce T cell responses in a manner that is restricted to non-classical MHC class I molecules. These responses are uncoupled from inflammation and highly distinct from pathogen-induced cells. Commensal-specific T cells express a defined gene signature that is characterized by expression of effector genes together with immunoregulatory and tissue-repair signatures. As such, non-classical MHCI-restricted commensal-specific immune responses not only promoted protection to pathogens, but also accelerated skin wound closure. Thus, the microbiota can induce a highly physiological and pleiotropic form of adaptive immunity that couples antimicrobial function with tissue repair. Our work also reveals that non-classical MHC class I molecules, an evolutionarily ancient arm of the immune system, can promote homeostatic immunity to the microbiota.
- Published
- 2018
48. Wild Mouse Gut Microbiota Promotes Host Fitness and Improves Disease Resistance
- Author
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Kazuyo Takeda, Stephan P. Rosshart, Davide Angeletti, Andrew P. Morgan, Nadim J. Ajami, Diane S. Hutchinson, Brian G. Vassallo, Heather D. Hickman, Barbara Rehermann, Giorgio Trinchieri, John A. McCulloch, Fernando Pardo-Manuel de Villena, Jonathan H. Badger, and Jonathan W. Yewdell
- Subjects
Male ,0301 basic medicine ,Carcinogenesis ,Animals, Wild ,Inflammation ,Gut flora ,Plant disease resistance ,Article ,General Biochemistry, Genetics and Molecular Biology ,Virus ,Microbiology ,Mice ,03 medical and health sciences ,Peromyscus ,0302 clinical medicine ,Animals, Laboratory ,medicine ,Animals ,Microbiome ,Physiological Phenomenon ,Disease Resistance ,Maryland ,biology ,Host (biology) ,Laboratory mouse ,biology.organism_classification ,Gastrointestinal Microbiome ,Mice, Inbred C57BL ,030104 developmental biology ,Virus Diseases ,030220 oncology & carcinogenesis ,Female ,medicine.symptom - Abstract
Summary Laboratory mice, while paramount for understanding basic biological phenomena, are limited in modeling complex diseases of humans and other free-living mammals. Because the microbiome is a major factor in mammalian physiology, we aimed to identify a naturally evolved reference microbiome to better recapitulate physiological phenomena relevant in the natural world outside the laboratory. Among 21 distinct mouse populations worldwide, we identified a closely related wild relative to standard laboratory mouse strains. Its bacterial gut microbiome differed significantly from its laboratory mouse counterpart and was transferred to and maintained in laboratory mice over several generations. Laboratory mice reconstituted with natural microbiota exhibited reduced inflammation and increased survival following influenza virus infection and improved resistance against mutagen/inflammation-induced colorectal tumorigenesis. By demonstrating the host fitness-promoting traits of natural microbiota, our findings should enable the discovery of protective mechanisms relevant in the natural world and improve the modeling of complex diseases of free-living mammals. Video Abstract
- Published
- 2017
49. Hepatitis C virus versus innate and adaptive immune responses: a tale of coevolution and coexistence
- Author
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Barbara Rehermann
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T-Lymphocytes ,Hepacivirus ,Hepatitis C virus ,chemical and pharmacologic phenomena ,medicine.disease_cause ,Immune system ,Immunity ,medicine ,Animals ,Humans ,Coevolution ,biology ,Vaccination ,virus diseases ,Dendritic Cells ,General Medicine ,Hepatitis C ,biochemical phenomena, metabolism, and nutrition ,medicine.disease ,biology.organism_classification ,Biological Evolution ,Virology ,Immunity, Innate ,Killer Cells, Natural ,Antibody Formation ,Mutation ,Immunology ,Disease Progression ,Hepatocytes ,Science in Medicine ,Viral hepatitis - Abstract
Since the identification of the hepatitis C virus (HCV) 20 years ago, much progress has been made in our understanding of its life cycle and interaction with the host immune system. Much has been learned from HCV itself, which, via decades of coevolution, gained an intricate knowledge of host innate and adaptive immune responses and developed sophisticated ways to preempt, subvert, and antagonize them. This review discusses the clinical, virological, and immunological features of acute and chronic hepatitis C and the role of the immune response in spontaneous and treatment-induced HCV clearance.
- Published
- 2009
50. The Accelerating Pace of HCV Research: A Summary of the 15th International Symposium on Hepatitis C Virus and Related Viruses
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Stanley M. Lemon, Michael Gale, Robert E. Lanford, Brett D. Lindenbach, Matthew J. Evans, Volker Lohmann, Barbara Rehermann, and Kyong-Mi Chang
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Carcinoma, Hepatocellular ,Hepacivirus ,Hepatitis C virus ,education ,Library science ,medicine.disease_cause ,Article ,medicine ,Humans ,Pace ,Hepatology ,biology ,Virus Assembly ,Liver Neoplasms ,Vaccination ,Gastroenterology ,Hepatitis C ,medicine.disease ,biology.organism_classification ,Virology ,Immunity, Innate ,humanities ,RNA, Viral ,Programmed death 1 - Abstract
Almost 800 research scientists convened in San Antonio in early October of 2008 to share recent results and new insights concerning hepatitis C virus (HCV). The 15th International Symposium on Hepatitis C Virus and Related Viruses opened with a mini-symposium recognizing progress made over the past 20 years since the discovery of HCV. This was followed by 10 keynote talks, and 61 oral and 379 poster presentations over the succeeding 4 days. Our intent is to succinctly summarize the most notable findings reported, a task made extraordinarily difficult by the volume, diversity and quality of science presented. At best, this cursory overview vividly demonstrates the robust pace of the research that is unraveling the mysteries of this unique and potentially deadly human pathogen.
- Published
- 2009
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