16 results on '"Muñoz, Elías"'
Search Results
2. Differential Changes in Inflammatory Mononuclear Phagocyte and T-Cell Profiles within Psoriatic Skin during Treatment with Guselkumab vs. Secukinumab
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Catherine Maari, Marika Sarfati, Robert Bissonnette, Shunya Mashiko, Kristian Reich, Ya-Ching M. Hsieh, Andrew Blauvelt, Ernesto J. Muñoz-Elías, Julianty Angsana, Manuel Rubio, and Heena Mehta
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0301 basic medicine ,Adult ,Male ,Regulatory T cell ,T cell ,Dermatology ,Cell Separation ,Antibodies, Monoclonal, Humanized ,Biochemistry ,Monocytes ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,T-Lymphocyte Subsets ,medicine ,Macrophage ,Humans ,Psoriasis ,IL-2 receptor ,Molecular Biology ,Aged ,Skin ,Chemistry ,FOXP3 ,Cell Biology ,Mononuclear phagocyte system ,Dendritic cell ,Middle Aged ,Flow Cytometry ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Immunology ,Female ,CD8 - Abstract
Cellular sources of IL-23 and IL-17A driving skin inflammation in psoriasis remain unclear. Using high-dimensional unsupervised flow cytometry analysis, mononuclear phagocytes and T cells were examined in the same lesions of patients before and during guselkumab (IL-23p19 blocker) or secukinumab (IL-17A blocker) treatment. Among CD11c+HLA-DR+ mononuclear phagocytes, CD64brightCD163−CD14brightCD1c−CD1a‒ inflammatory monocyte‒like cells were the predominant IL-23–producing cells and, together with CD64−CD163−CD14−IL-23p19−TNF-α+ inflammatory dendritic cell‒like cells, were increased in lesional compared with those in nonlesional skin taken from the same patient. Within T cells, CD8+CD49a+ and/or CD103+ tissue-resident memory T cells, CD4+CD25+FoxP3+ regulatory T cells, and CD4+CD49a−CD103− T cells were increased. Moreover, CD4+CD49a−CD103− T cells and the relatively rare CD8+ memory T cells equally contributed to IL-17A production. Both treatments decreased the frequencies of inflammatory monocyte‒like, inflammatory dendritic cell‒like, and CD4+CD49a−CD103− T cells. In contrast, guselkumab reduced memory T cells while maintaining regulatory T cells and vice versa for secukinumab. Neither drug modified the frequencies of IL-17A+IL‒17F+/– CD4+ or CD8+ T cells. This study reveals the identity of the major IL-23+ mononuclear phagocyte and IL-17+ T-cell subsets in psoriatic skin lesions and paves the way for a better understanding of the mode of action of drugs targeting the IL-23/IL-17A pathway in psoriasis.
- Published
- 2020
3. Longitudinal Study of the Psoriasis-Associated Skin Microbiome during Therapy with Ustekinumab in a Randomized Phase 3b Clinical Trial
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Michael A. Loesche, Kamyar Farahi, Elizabeth A. Grice, Amanda S. Tyldsley, Samuel E. DePrimo, Marc Chevrier, Carrie Brodmerkel, Joseph Horwinski, Kristina Callis Duffin, Steven Fakharzadeh, Kimberly A. Capone, Kevin D. Smith, Andrew Blauvelt, Ernesto J. Muñoz-Elías, and Bidisha Dasgupta
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Adult ,Male ,0301 basic medicine ,Adolescent ,Dermatology ,Disease ,Biochemistry ,Pathogenesis ,Young Adult ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Psoriasis ,Ustekinumab ,medicine ,Genetic predisposition ,Humans ,Microbiome ,Molecular Biology ,Aged ,Retrospective Studies ,Skin ,Aged, 80 and over ,Innate immune system ,Bacteria ,Dose-Response Relationship, Drug ,business.industry ,Microbiota ,Cell Biology ,Middle Aged ,medicine.disease ,RNA, Bacterial ,Cross-Sectional Studies ,030104 developmental biology ,Immunology ,Etiology ,Female ,Dermatologic Agents ,business ,Follow-Up Studies ,medicine.drug - Abstract
Plaque psoriasis, a chronic inflammatory disease primarily affecting the skin, is thought to have a multifactorial etiology, including innate immune system dysregulation, environmental triggers, and genetic susceptibility. We sought to further understand the role of skin microbiota in psoriasis pathogenesis, as well as their response to therapy. We systematically analyzed dynamic microbiota colonizing psoriasis lesions and adjacent nonlesional skin in 114 patients prior to and during ustekinumab treatment in a phase 3b clinical trial. By sequencing the bacterial 16S ribosomal RNA gene from skin swab samples obtained at six anatomical sites, we identified minor, site-specific differences in microbial diversity and composition between pretreatment lesional and nonlesional skin. During therapy, microbial communities within lesional and nonlesional skin diverged, and body-site dispersion increased, reflecting microbial skin site-specificity. Microbiota demonstrated greater pretreatment heterogeneity in psoriatic lesions than in nonlesional skin, and variance increased as treatment progressed. Microbiota colonizing recurrent lesions did not overlap with pretreatment lesional microbiota, suggesting colonization patterns varied between initial and recurrent psoriatic lesions. While plaque psoriasis does not appear to be associated with specific microbes and/or microbial diversity, this large dataset provides insight into microbial variation associated with (i) disease in different body locations, (ii) initial versus recurrent lesions, and (iii) anti-IL12/23 therapy.
- Published
- 2018
4. Nasopharyngeal Exposure to Streptococcus pneumoniae Induces Extended Age-Dependent Protection against Pulmonary Infection Mediated by Antibodies and CD138+ Cells
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Nalat Siwapornchai, John M. Leong, Nang H. Tin Maung, Andrew Camilli, Rachel M. Gerstein, Elsa N. Bou Ghanem, Aaron E. Goodwin, Ernesto J. Muñoz-Elías, and Stacie Clark
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0301 basic medicine ,Lung ,biology ,business.industry ,Immunology ,medicine.disease_cause ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Immune system ,Immunity ,Streptococcus pneumoniae ,biology.protein ,Immunology and Allergy ,Medicine ,Secretion ,Bone marrow ,Antibody ,business ,CD8 ,030215 immunology - Abstract
Streptococcus pneumoniae commonly resides asymptomatically in the nasopharyngeal (NP) cavity of healthy individuals but can cause life-threatening pulmonary and systemic infections, particularly in the elderly. NP colonization results in a robust immune response that protects against invasive infections. However, the duration, mechanism, and cellular component of such responses are poorly understood. In this study, we found that repeated NP exposure of mice to S. pneumoniae TIGR4 strain results in pneumococcal-specific Ab responses that protect against lethal lung challenge. Abs were necessary and sufficient for protection because Ab-deficient μMT mice did not develop postexposure protection, only becoming resistant to lung infection after transfer of immune sera from NP-exposed mice. T cells contributed to immunity at the time of NP exposure, but neither CD4+ nor CD8+ T cells were required. The protective activity was detectable 20 wk after exposure and was maintained in irradiated mice, suggesting involvement of long-lived Ab-secreting cells (ASC), which are radioresistant and secrete Abs for extended periods of time in the absence of T cells or persistent Ag. CD138+ bone marrow cells, likely corresponding to long-lived ASC, were sufficient to confer protection. NP exposure of aged mice failed to protect against subsequent lung infection despite eliciting a robust Ab response. Furthermore, transfer of CD138+ bone marrow cells or sera from NP-exposed old mice failed to protect naive young mice. These findings suggest that NP exposure elicits extended protection against pneumococcal lung infection by generating long-lived CD138+ ASC and that the protective efficacy of these responses declines with age.
- Published
- 2018
5. Kv1.3 channel Blockade Modulates the effector Function of B cells in granulomatosis with Polyangiitis
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Judith Land, Lucas L. Lintermans, Coen A. Stegeman, Ernesto J. Muñoz-Elías, Eric J. Tarcha, Shawn P. Iadonato, Peter Heeringa, Abraham Rutgers, Wayel H. Abdulahad, Groningen Kidney Center (GKC), and Translational Immunology Groningen (TRIGR)
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0301 basic medicine ,lcsh:Immunologic diseases. Allergy ,ANCA-ASSOCIATED VASCULITIS ,Regulatory B cells ,medicine.medical_treatment ,Immunology ,Naive B cell ,PATHOGENESIS ,PRIMARY SJOGRENS-SYNDROME ,03 medical and health sciences ,INADEQUATE RESPONSE ,0302 clinical medicine ,Proteinase 3 ,medicine ,ION CHANNELS ,Immunology and Allergy ,Kv1.3 potassium channels ,Interferon gamma ,RITUXIMAB ,antineutrophil cytoplasmic antibody ,B cell ,Original Research ,Anti-neutrophil cytoplasmic antibody ,030203 arthritis & rheumatology ,B cells ,business.industry ,Autoantibody ,Molecular biology ,cytokines ,3. Good health ,RHEUMATOID-ARTHRITIS ,030104 developmental biology ,medicine.anatomical_structure ,Cytokine ,DEPRESSED PERCENTAGE ,MEMORY B ,PHASE-II ,business ,lcsh:RC581-607 ,medicine.drug ,granulomatosis and polyangiitis - Abstract
B cells are central to the pathogenesis of granulomatosis with polyangiitis (GPA), exhibiting both (auto) antibody-dependent and -independent properties. Class-switched memory B cells in particular are a major source of pathogenic autoantibodies. These cells are characterized by high expression levels of Kv1.3 potassium channels, which may offer therapeutic potential for Kv1.3 blockade. In this study, we investigated the effect of the highly potent Kv1.3 blocker ShK-186 on B cell properties in GPA in vitro. Circulating B cell subsets were determined from 33 GPA patients and 17 healthy controls (HCs). Peripheral blood mononuclear cells (PBMCs) from GPA patients, and HCs were stimulated in vitro in the presence and absence of ShK-186. The production of total and antineutrophil cytoplasmic antibodies targeting proteinase 3 (PR3-ANCA) IgG was analyzed by enzyme-linked immunosorbent assay and Phadia EliA, respectively. In addition, effects of ShK-186 on B cell proliferation and cytokine production were determined by flow cytometry. The frequency of circulating switched and unswitched memory B cells was decreased in GPA patients as compared to HC. ShK-186 suppressed the production of both total and PR3-ANCA IgG in stimulated PBMCs. A strong decrease in production of tumor necrosis factor alpha (TNF alpha), interleukin (IL)-2, and interferon gamma was observed upon ShK-186 treatment, while effects on IL-10 production were less pronounced. As such, ShK-186 modulated the TNF alpha/IL-10 ratio among B cells, resulting in a relative increase in the regulatory B cell pool. ShK-186 modulates the effector functions of B cells in vitro by decreasing autoantibody and pro-inflammatory cytokine production. Kv1.3 channel blockade may hold promise as a novel therapeutic strategy in GPA and other B cell-mediated autoimmune disorders.
- Published
- 2017
6. Correction: Nasopharyngeal Exposure to Streptococcus pneumoniae Induces Extended Age-Dependent Protection against Pulmonary Infection Mediated by Antibodies and CD138+ Cells
- Author
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Elsa N. Bou Ghanem, Nang H. Tin Maung, Nalat Siwapornchai, Aaron E. Goodwin, Stacie Clark, Ernesto J. Muñoz-Elías, Andrew Camilli, Rachel M. Gerstein, and John M. Leong
- Subjects
Immunology ,Immunology and Allergy - Published
- 2018
7. Durable Pharmacological Responses from the Peptide ShK-186, a Specific Kv1.3 Channel Inhibitor That Suppresses T Cell Mediators of Autoimmune Disease
- Author
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Amy Banks, David Bailey, K. George Chandy, Shawn P. Iadonato, James Sams, Greg W. Ruppert, Eric J. Tarcha, Sanjeev K. Upadhyay, Luz M. Londono, Kayla Norton, Richard Slauter, Brian I. Knapp, Ernesto J. Muñoz-Elías, Michael W. Pennington, Indra W. Tjong, Zachary Hansen, Scott E. Boley, Dustin Kentala, Victor Chi, Hai M. Nguyen, Xueyou Hu, and Christine Beeton
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Encephalomyelitis, Autoimmune, Experimental ,T-Lymphocytes ,medicine.medical_treatment ,T cell ,Arthritis ,Peripheral blood mononuclear cell ,Absorption ,Autoimmune Diseases ,Rats, Sprague-Dawley ,Inhibitory Concentration 50 ,Drug Discovery and Translational Medicine ,Pharmacokinetics ,Potassium Channel Blockers ,Animals ,Humans ,Medicine ,Tissue Distribution ,Saimiri ,Pharmacology ,Autoimmune disease ,Kv1.3 Potassium Channel ,Dose-Response Relationship, Drug ,business.industry ,Experimental autoimmune encephalomyelitis ,Proteins ,medicine.disease ,Rats ,Disease Models, Animal ,Macaca fascicularis ,Cytokine ,medicine.anatomical_structure ,Rheumatoid arthritis ,Immunology ,Leukocytes, Mononuclear ,Cytokines ,Molecular Medicine ,Female ,business - Abstract
The Kv1.3 channel is a recognized target for pharmaceutical development to treat autoimmune diseases and organ rejection. ShK-186, a specific peptide inhibitor of Kv1.3, has shown promise in animal models of multiple sclerosis and rheumatoid arthritis. Here, we describe the pharmacokinetic-pharmacodynamic relationship for ShK-186 in rats and monkeys. The pharmacokinetic profile of ShK-186 was evaluated with a validated high-performance liquid chromatography-tandem mass spectrometry method to measure the peptide's concentration in plasma. These results were compared with single-photon emission computed tomography/computed tomography data collected with an 111In-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-conjugate of ShK-186 to assess whole-blood pharmacokinetic parameters as well as the peptide's absorption, distribution, and excretion. Analysis of these data support a model wherein ShK-186 is absorbed slowly from the injection site, resulting in blood concentrations above the Kv1.3 channel-blocking IC50 value for up to 7 days in monkeys. Pharmacodynamic studies on human peripheral blood mononuclear cells showed that brief exposure to ShK-186 resulted in sustained suppression of cytokine responses and may contribute to prolonged drug effects. In delayed-type hypersensitivity, chronic relapsing-remitting experimental autoimmune encephalomyelitis, and pristane-induced arthritis rat models, a single dose of ShK-186 every 2 to 5 days was as effective as daily administration. ShK-186's slow distribution from the injection site and its long residence time on the Kv1.3 channel contribute to the prolonged therapeutic effect of ShK-186 in animal models of autoimmune disease.
- Published
- 2012
8. Carbon metabolism of intracellular bacteria
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Ernesto J. Muñoz-Elías and John D. McKinney
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Microorganism ,Immunology ,Microbial metabolism ,medicine.disease_cause ,Microbiology ,Citric Acid ,Salmonella ,Virology ,Escherichia coli ,medicine ,Humans ,Axenic ,Bacteria ,biology ,Gram Negative Bacillus ,Intracellular parasite ,Fatty Acids ,Gluconeogenesis ,Pathogenic bacteria ,Bacterial Infections ,Mycobacterium tuberculosis ,biology.organism_classification ,Listeria monocytogenes ,Carbon ,Carbohydrate Metabolism - Abstract
Bacterial metabolism has been studied intensively since the first observations of these 'animalcules' by Leeuwenhoek and their isolation in pure cultures by Pasteur. Metabolic studies have traditionally focused on a small number of model organisms, primarily the Gram negative bacillus Escherichia coli, adapted to artificial culture conditions in the laboratory. Comparatively little is known about the physiology and metabolism of wild microorganisms living in their natural habitats. For approximately 500-1000 species of commensals and symbionts, and a smaller number of pathogenic bacteria, that habitat is the human body. Emerging evidence suggests that the metabolism of bacteria grown in vivo differs profoundly from their metabolism in axenic cultures.
- Published
- 2006
9. Safety and pharmacodynamics of dalazatide, a Kv1.3 channel inhibitor, in the treatment of plaque psoriasis: A randomized phase 1b trial
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James G. Kruger, Peter Probst, Shawn P. Iadonato, Chelsea M. Olsen, David Peckham, Ernesto J. Muñoz-Elías, and Eric J. Tarcha
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Male ,0301 basic medicine ,Physiology ,lcsh:Medicine ,Pathology and Laboratory Medicine ,Gastroenterology ,Memory T cells ,law.invention ,White Blood Cells ,0302 clinical medicine ,Randomized controlled trial ,Animal Cells ,law ,Blood plasma ,Medicine and Health Sciences ,lcsh:Science ,Kv1.3 Potassium Channel ,Multidisciplinary ,T Cells ,Middle Aged ,Body Fluids ,Blood ,Treatment Outcome ,medicine.anatomical_structure ,Physiological Parameters ,Research Design ,Female ,Cellular Types ,Anatomy ,Research Article ,Adult ,medicine.medical_specialty ,Clinical Research Design ,Immune Cells ,Immunology ,Research and Analysis Methods ,Placebo ,Blood Plasma ,Autoimmune Diseases ,Hypesthesia ,03 medical and health sciences ,Signs and Symptoms ,Double-Blind Method ,Diagnostic Medicine ,Psoriasis Area and Severity Index ,Internal medicine ,Psoriasis ,Potassium Channel Blockers ,medicine ,Humans ,Paresthesia ,Adverse effect ,Blood Cells ,business.industry ,Body Weight ,lcsh:R ,Biology and Life Sciences ,Proteins ,Cell Biology ,medicine.disease ,Surgery ,030104 developmental biology ,Pharmacodynamics ,Lesions ,Clinical Immunology ,lcsh:Q ,Adverse Events ,Clinical Medicine ,business ,Memory T cell ,030217 neurology & neurosurgery - Abstract
Background Dalazatide is a specific inhibitor of the Kv1.3 potassium channel. The expression and function of Kv1.3 channels are required for the function of chronically activated memory T cells, which have been shown to be key mediators of autoimmune diseases, including psoriasis. Objective The primary objective was to evaluate the safety of repeat doses of dalazatide in adult patients with mild-to-moderate plaque psoriasis. Secondary objectives were to evaluate clinical proof of concept and the effects of dalazatide on mediators of inflammation in the blood and on chronically activated memory T cell populations. Methods Patients (n = 24) were randomized 5:5:2 to receive dalazatide at 30 mcg/dose, 60 mcg/dose, or placebo twice weekly by subcutaneous injection (9 doses total). Safety was assessed on the basis of physical and neurological examination and laboratory testing. Clinical assessments included body-surface area affected, Psoriasis Area and Severity Index (PASI), and investigator and patient questionnaires. Results The most common adverse events were temporary mild (Grade 1) hypoesthesia (n = 20; 75% placebo, 85% dalazatide) and paresthesia (n = 15; 25% placebo, 70% dalazatide) involving the hands, feet, or perioral area. Nine of 10 patients in the 60 mcg/dose group had a reduction in their PASI score between baseline and Day 32, and the mean reduction in PASI score was significant in this group (P < 0.01). Dalazatide treatment reduced the plasma levels of multiple inflammation markers and reduced the expression of T cell activation markers on peripheral blood memory T cells. Limitations The study was small and drug treatment was for a short duration (4 weeks). Conclusion This study indicates that dalazatide is generally well tolerated and can improve psoriatic skin lesions by modulating T cell surface and activation marker expression and inhibiting mediators of inflammation in the blood. Larger studies of longer duration are warranted.
- Published
- 2017
10. Bacterial Persistence: Strategies for Survival
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Ernesto J. Muñoz-Elías and John D. McKinney
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Humoral immunity ,Immunology ,Neisseria gonorrhoeae ,medicine ,Antigenic variation ,Biofilm ,Biology ,medicine.disease_cause ,Acquired immune system ,Bacterial outer membrane ,Pilus ,Diplococcus ,Microbiology - Abstract
This chapter focuses on a few organisms as paradigms of persistence strategies. Programmed rearrangement of genes encoding surface antigens (antigenic variation) is essential for the evasion of adaptive humoral immunity by extracellular, blood-borne pathogens such as the Borrelia spp. that cause relapsing fever (RF) and Lyme disease (LD). Gonorrhea, caused by the gram-negative diplococcus Neisseria gonorrhoeae, is one of the most prevalent sexually transmitted diseases of humans-every year, one million new cases are reported in the United States alone. Variation of several cell surface components of the gonococcus-notably, the pili, outer membrane Opa proteins, and LOS-is controlled by distinct and complex mechanisms. Despite the manifest importance of persistence in the pathogenesis of tuberculosis (TB), little is known about the mechanisms that promote mycobacterial persistence in vivo. Indeed, reactive oxygen intermediates (ROI) detoxification mediated by the KatG catalase is essential for bacterial persistence in mice following induction of adaptive immunity. One of the most familiar and complex types of medically relevant biofilm is dental plaque, comprising hundreds of microbial species. The study of microbial biofilms and their role in persistent infections is still at an early stage. The environmental signals that promote biofilm formation and dissolution and the signals that the bacteria use to communicate with each other are just beginning to be deciphered.
- Published
- 2014
11. Persistence of Mycobacterium tuberculosis in macrophages and mice requires the glyoxylate shunt enzyme isocitrate lyase
- Author
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Bing Chen, Ernesto J. Muñoz-Elías, Dana L. Swenson, William R. Jacobs, David G. Russell, John D. McKinney, James C. Sacchettini, Kerstin Höner zu Bentrup, Wal Tsing Chan, and Andras Miczak
- Subjects
Cellular immunity ,Tuberculosis ,Recombinant Fusion Proteins ,Glyoxylate cycle ,Virulence ,Microbiology ,Mycobacterium tuberculosis ,Mice ,Immune system ,Bacterial Proteins ,medicine ,Animals ,Lung ,Pathogen ,Mice, Knockout ,Mice, Inbred BALB C ,Multidisciplinary ,biology ,Macrophages ,Fatty Acids ,Isocitrate lyase ,Macrophage Activation ,medicine.disease ,biology.organism_classification ,Isocitrate Lyase ,Mice, Inbred C57BL ,Mutagenesis ,Immunology - Abstract
Mycobacterium tuberculosis claims more human lives each year than any other bacterial pathogen. Infection is maintained in spite of acquired immunity and resists eradication by antimicrobials. Despite an urgent need for new therapies targeting persistent bacteria, our knowledge of bacterial metabolism throughout the course of infection remains rudimentary. Here we report that persistence of M. tuberculosis in mice is facilitated by isocitrate lyase (ICL), an enzyme essential for the metabolism of fatty acids. Disruption of the icl gene attenuated bacterial persistence and virulence in immune-competent mice without affecting bacterial growth during the acute phase of infection. A link between the requirement for ICL and the immune status of the host was established by the restored virulence of delta icl bacteria in interferon-gamma knockout mice. This link was apparent at the level of the infected macrophage: Activation of infected macrophages increased expression of ICL, and the delta icl mutant was markedly attenuated for survival in activated but not resting macrophages. These data suggest that the metabolism of M. tuberculosis in vivo is profoundly influenced by the host response to infection, an observation with important implications for the treatment of chronic tuberculosis.
- Published
- 2000
12. Immunological Aspects of Chest Diseases: The Case of Tuberculosis
- Author
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Wilkinson, Robert J. Ph.D., Frcp and Ernesto Muñoz-Elías
- Subjects
Bronchiectasis ,Lung ,biology ,business.industry ,respiratory system ,Immunoglobulin E ,medicine.disease ,Mucus ,Microbiology ,Immune system ,medicine.anatomical_structure ,Lymphatic system ,Immunology ,biology.protein ,medicine ,Antibody ,business ,Respiratory tract - Abstract
INTRODUCTION The respiratory tract is one of the first portals of entry for many viral and bacterial microorganisms. The local defense systems are generally sufficient to handle most invading microorganisms in healthy individuals but if the lung is damaged by bronchiectasis or fibrosis, the infecting microorganisms are able to establish an infection, cross the epithelial layer, and cause invasive disease. The respiratory tract has two main compartments. The first is the airways, which extend from the nose to the terminal bronchioli. The second area is the alveoli in the lung tissue. The airways' defenses include many features such as ciliary movement, mucus, antimicrobial proteins, and rapid arrival of neutrophils whose combined action make it difficult for organisms to establish an infection. The access to the alveoli is also generally limited to very small inhaled particles. In the alveoli, invading microorganisms encounter resident alveolar macrophages that play a major role in engulfing and killing invaders. The lung has its own immune system, which is known as bronchus-associated lymphoid tissue. Antigen-specific immune responses are generated at these sites, which, similarly to the Peyer's patches in the intestine, contain dendritic cells (DCs), which are the main antigen-presenting cells, as well as T and B cells, the latter organized into B-cell follicles, as well as macrophages. Immune responses occur in response to infections or injury to the tract. The main antibodies found in respiratory tract secretions are IgA and IgG. However, B cells producing IgE and IgG are also found in the lung.
- Published
- 2009
13. Isolation of Streptococcus pneumoniae Biofilm Mutants and Their Characterization during Nasopharyngeal Colonization▿ †
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Ernesto J. Muñoz-Elías, Joan Marcano, and Andrew Camilli
- Subjects
Immunology ,Mutant ,Biology ,medicine.disease_cause ,Microbiology ,Polymerase Chain Reaction ,Pilus ,Pneumococcal Infections ,Mice ,Nasopharynx ,Streptococcus pneumoniae ,medicine ,Animals ,Adhesins, Bacterial ,Choline binding ,Bacterial Capsules ,Biofilm ,biochemical phenomena, metabolism, and nutrition ,biology.organism_classification ,Molecular Pathogenesis ,Bacterial adhesin ,Mice, Inbred C57BL ,Infectious Diseases ,Genes, Bacterial ,Biofilms ,Mutation ,Parasitology ,Female ,Efflux ,Bacteria - Abstract
Asymptomatic colonization of the nasopharynx by Streptococcus pneumoniae precedes pneumococcal disease, yet pneumococcal colonization factors remain poorly understood. Many bacterial infections involve biofilms which protect bacteria from host defenses and antibiotics. To gain insight into the genetics of biofilm formation by S. pneumoniae , we conducted an in vitro screen for biofilm-altered mutants with the serotype 4 clinical isolate TIGR4. In a first screen of 6,000 mariner transposon mutants, we repeatedly isolated biofilm-overproducing acapsular mutants, suggesting that the capsule was antagonistic to biofilm formation. Therefore, we screened 6,500 additional transposon mutants in an S. pneumoniae acapsular background. Following this approach, we isolated 69 insertions in 49 different genes. The collection of mutants includes genes encoding bona fide and putative choline binding proteins, adhesins, synthases of membrane and cell wall components, extracellular and cell wall proteases, efflux pumps, ABC and PTS transporters, and transcriptional regulators, as well as several conserved and novel hypothetical proteins. Interestingly, while four insertions mapped to rrgA , encoding a subunit of a recently described surface pilus, rrgB and rrgC (encoding the other two pilus subunits) mutants had no biofilm defects, implicating the RrgA adhesin but not the pilus structure per se in biofilm formation. To correlate our findings to the process of colonization, we transferred a set of 29 mutations into the wild-type encapsulated strain and then tested the fitness of the mutants in vivo. Strikingly, we found that 23 of these mutants were impaired for nasopharyngeal colonization, thus establishing a link between biofilm formation and colonization.
- Published
- 2008
14. Safety and pharmacodynamics of dalazatide, a Kv1.3 channel inhibitor, in the treatment of plaque psoriasis: A randomized phase 1b trial.
- Author
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Tarcha, Eric J., Olsen, Chelsea M., Probst, Peter, Peckham, David, Muñoz-Elías, Ernesto J., Kruger, James G., and Iadonato, Shawn P.
- Subjects
PHARMACODYNAMICS ,POTASSIUM antagonists ,PEPTIDOMIMETICS ,EFFECT of drugs on T cells ,CLINICAL trials ,THERAPEUTICS - Abstract
Background: Dalazatide is a specific inhibitor of the Kv1.3 potassium channel. The expression and function of Kv1.3 channels are required for the function of chronically activated memory T cells, which have been shown to be key mediators of autoimmune diseases, including psoriasis. Objective: The primary objective was to evaluate the safety of repeat doses of dalazatide in adult patients with mild-to-moderate plaque psoriasis. Secondary objectives were to evaluate clinical proof of concept and the effects of dalazatide on mediators of inflammation in the blood and on chronically activated memory T cell populations. Methods: Patients (n = 24) were randomized 5:5:2 to receive dalazatide at 30 mcg/dose, 60 mcg/dose, or placebo twice weekly by subcutaneous injection (9 doses total). Safety was assessed on the basis of physical and neurological examination and laboratory testing. Clinical assessments included body-surface area affected, Psoriasis Area and Severity Index (PASI), and investigator and patient questionnaires. Results: The most common adverse events were temporary mild (Grade 1) hypoesthesia (n = 20; 75% placebo, 85% dalazatide) and paresthesia (n = 15; 25% placebo, 70% dalazatide) involving the hands, feet, or perioral area. Nine of 10 patients in the 60 mcg/dose group had a reduction in their PASI score between baseline and Day 32, and the mean reduction in PASI score was significant in this group (P < 0.01). Dalazatide treatment reduced the plasma levels of multiple inflammation markers and reduced the expression of T cell activation markers on peripheral blood memory T cells. Limitations: The study was small and drug treatment was for a short duration (4 weeks). Conclusion: This study indicates that dalazatide is generally well tolerated and can improve psoriatic skin lesions by modulating T cell surface and activation marker expression and inhibiting mediators of inflammation in the blood. Larger studies of longer duration are warranted. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
15. Nasopharyngeal colonization by Streptococcus pneumoniae elicits long-lasting immune responses that confer protection from invasive lung infections (161.19)
- Author
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Nang Maung, Aaron Goodwin, Ernesto Muñoz-Elías, Andrew Camilli, Rachel Gerstein, and John Leong
- Subjects
Immunology ,Immunology and Allergy - Abstract
Streptococcus pneumoniae can cause life-threatening pulmonary and systemic infection, but resides usually harmlessly in the nasopharynx of many people. Humoral immunity is thought to be the primary defense against serious pneumococcal infection, and we hypothesized that nasopharyngeal colonization of mice may result in the generation of an antibody response that provides long-term protection against lung infection. In fact, we found that intranasal colonization elicited pneumococcal-specific antibody responses and protected from a S. pneumoniae lung challenge that is lethal in naive mice. B cells were required for protection, and transfer of immune sera from colonized mice protected naive mice. CD93-/- mice, which are deficient in long-term antibody secreting cells (ASC), had fewer pneumococcal-specific bone marrow ASC after intranasal colonization and did not survive lung challenge. T cells were required to generate a fully protective response, but elimination of CD4+ T cells just prior to lung challenge did not compromise. These data are consistent with the hypothesis that CD4+ T cells promote the development of post-colonization immunity but are not needed to sustain the response that provides protection from lung challenge. These results stand in contrast to the T-cell independent antibody responses that are sufficient to protect mice from systemic infection, and have implications for development of effective vaccines.
- Published
- 2011
16. Replication dynamics of Mycobacterium tuberculosis in chronically infected mice
- Author
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Ernesto J. Muñoz-Elías, Wai-Tsing Chan, John D. McKinney, Tania Botha, Juliano Timm, and James Gomez
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Tuberculosis ,Immunology ,Colony Count, Microbial ,Bacterial growth ,Microbiology ,Mycobacterium tuberculosis ,Mice ,Immunity ,medicine ,Animals ,Lung ,Pathogen ,biology ,Bacterial Infections ,Chromosomes, Bacterial ,Antimicrobial ,medicine.disease ,biology.organism_classification ,Virology ,Mice, Inbred C57BL ,Chronic infection ,Infectious Diseases ,Chronic Disease ,Parasitology ,Bacteria - Abstract
The dynamics of host-pathogen interactions have important implications for the design of new antimicrobial agents to treat chronic infections such as tuberculosis (TB), which is notoriously refractory to conventional drug therapy. In the mouse model of TB, an acute phase of exponential bacterial growth in the lungs is followed by a chronic phase characterized by relatively stable numbers of bacteria. This equilibrium could be static, with little ongoing replication, or dynamic, with continuous bacterial multiplication balanced by bacterial killing. A static model predicts a close correspondence between “viable counts” (live bacteria) and “total counts” (live plus dead bacteria) in the lungs over time. A dynamic model predicts the divergence of total counts and viable counts over time due to the accumulation of dead bacteria. Here, viable counts are defined as bacterial CFU enumerated by plating lung homogenates; total counts are defined as bacterial chromosome equivalents (CEQ) enumerated by using quantitative real-time PCR. We show that the viable and total bacterial counts in the lungs of chronically infected mice do not diverge over time. Rapid degradation of dead bacteria is unlikely to account for the stability of bacterial CEQ numbers in the lungs over time, because treatment of mice with isoniazid for 8 weeks led to a marked reduction in the number of CFU without reducing the number of CEQ. These observations support the hypothesis that the stable number of bacterial CFU in the lungs during chronic infection represents a static equilibrium between host and pathogen.
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