315 results on '"DeRisi JL"'
Search Results
2. Novel Picornavirus Associated with Avian Keratin Disorder in Alaskan Birds
- Author
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Derisi, Joseph, Zylberberg, M, Van, C, Dumbacher, JP, Handel, CM, Tihan, T, and DeRisi, JL
- Published
- 2016
3. Diagnosing Balamuthia mandrillaris Encephalitis With Metagenomic Deep Sequencing
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Wilson, MR, Shanbhag, NM, Reid, MJ, Singhal, NS, Gelfand, JM, Sample, HA, Benkli, B, O'Donovan, BD, Ali, IKM, Keating, MK, Dunnebacke, TH, Wood, MD, Bollen, A, and Derisi, JL
- Abstract
© 2015 The Authors Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association. Objective: Identification of a particular cause of meningoencephalitis can be challenging owing to the myriad bacteria, viruses, fungi, and parasites that can produce overlapping clinical phenotypes, frequently delaying diagnosis and therapy. Metagenomic deep sequencing (MDS) approaches to infectious disease diagnostics are known for their ability to identify unusual or novel viruses and thus are well suited for investigating possible etiologies of meningoencephalitis. Methods: We present the case of a 74-year-old woman with endophthalmitis followed by meningoencephalitis. MDS of her cerebrospinal fluid (CSF) was performed to identify an infectious agent. Results: Sequences aligning to Balamuthia mandrillaris ribosomal RNA genes were identified in the CSF by MDS. Polymerase chain reaction subsequently confirmed the presence of B. mandrillaris in CSF, brain tissue, and vitreous fluid from the patient's infected eye. B. mandrillaris serology and immunohistochemistry for free-living amoebas on the brain biopsy tissue were positive. Interpretation: The diagnosis was made using MDS after the patient had been hospitalized for several weeks and subjected to costly and invasive testing. MDS is a powerful diagnostic tool with the potential for rapid and unbiased pathogen identification leading to early therapeutic targeting.
- Published
- 2015
4. Profile hidden Markov models for the detection of viruses within metagenomic sequence data
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Derisi, Joseph, Pollard, Katherine, Skewes-Cox, P, Sharpton, TJ, Pollard, KS, and DeRisi, JL
- Abstract
Rapid, sensitive, and specific virus detection is an important component of clinical diagnostics. Massively parallel sequencing enables new diagnostic opportunities that complement traditional serological and PCR based techniques. While massively parallel
- Published
- 2014
5. Genome sequence of a bornavirus recovered from an African garter snake (Elapsoidea loveridgei)
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Derisi, Joseph, Stenglein, MD, Leavitt, EB, Abramovitch, MA, McGuire, JA, and DeRisi, JL
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integumentary system - Abstract
© 2014 Stenglein et al.Bornaviruses are known to infect mammals and birds, and they have been associated with disease in both groups of animals. Here, we report the genome sequence of a bornavirus identified in a wild-caught Loveridge's garter snake (Elaps
- Published
- 2014
6. The Kinase Regulator Mob1 Acts as a Patterning Protein for Stentor Morphogenesis
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Marshall, Wallace, Derisi, Joseph, Slabodnick, MM, Ruby, JG, Dunn, JG, Feldman, JL, DeRisi, JL, and Marshall, WF
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education - Abstract
Morphogenesis and pattern formation are vital processes in any organism, whether unicellular or multicellular. But in contrast to the developmental biology of plants and animals, the principles of morphogenesis and pattern formation in single cells remain
- Published
- 2014
7. Microfluidic affinity and ChIP-seq analyses converge on a conserved FOXP2-binding motif in chimp and human, which enables the detection of evolutionarily novel targets
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Li, Hao, Derisi, Joseph, Nelson, CS, Fuller, CK, Fordyce, PM, Greninger, AL, and DeRisi, JL
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otorhinolaryngologic diseases - Abstract
The transcription factor forkhead box P2 (FOXP2) is believed to be important in the evolution of human speech. A mutation in its DNA-binding domain causes severe speech impairment. Humans have acquired two coding changes relative to the conserved mammalian
- Published
- 2013
8. Bartonella quintana Deploys Host and Vector Temperature-Specific Transcriptomes
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Koehler, Jane, Derisi, Joseph, Abromaitis, S, Nelson, CS, Previte, D, Yoon, KS, Clark, JM, DeRisi, JL, and Koehler, JE
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bacteria ,bacterial infections and mycoses - Abstract
The bacterial pathogen Bartonella quintana is passed between humans by body lice. B. quintana has adapted to both the human host and body louse vector niches, producing persistent infection with high titer bacterial loads in both the host (up to 105 colony
- Published
- 2013
9. Identification and Manipulation of the Molecular Determinants Influencing Poliovirus Recombination
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Derisi, Joseph, Runckel, C, Westesson, O, Andino, R, and DeRisi, JL
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viruses - Abstract
The control and prevention of communicable disease is directly impacted by the genetic mutability of the underlying etiological agents. In the case of RNA viruses, genetic recombination may impact public health by facilitating the generation of new viral s
- Published
- 2013
10. PRICE: Software for the targeted assembly of components of (Meta) genomic sequence data
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Derisi, Joseph, Ruby, JG, Bellare, P, and DeRisi, JL
- Abstract
Low-cost DNA sequencing technologies have expanded the role for direct nucleic acid sequencing in the analysis of genomes, transcriptomes, and the metagenomes of whole ecosystems. Human and machine comprehension of such large datasets can be simplified via
- Published
- 2013
11. Optimization of diastereomeric dihydropyridines as antimalarials.
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Van Horn KS, Zhao Y, Parvatkar PT, Maier J, Mutka T, Lacrue A, Brockmeier F, Ebert D, Wu W, Casandra DR, Namelikonda N, Yacoub J, Sigal M, Knapp S, Floyd D, Waterson D, Burrows JN, Duffy J, DeRisi JL, Kyle DE, Guy RK, and Manetsch R
- Subjects
- Structure-Activity Relationship, Animals, Mice, Stereoisomerism, Parasitic Sensitivity Tests, Molecular Structure, Dose-Response Relationship, Drug, Humans, Antimalarials pharmacology, Antimalarials chemistry, Antimalarials chemical synthesis, Dihydropyridines pharmacology, Dihydropyridines chemistry, Dihydropyridines chemical synthesis, Plasmodium falciparum drug effects
- Abstract
The increase in research funding for the development of antimalarials since 2000 has led to a surge of new chemotypes with potent antimalarial activity. High-throughput screens have delivered several thousand new active compounds in several hundred series, including the 4,7-diphenyl-1,4,5,6,7,8-hexahydroquinolines, hereafter termed dihydropyridines (DHPs). We optimized the DHPs for antimalarial activity. Structure-activity relationship studies focusing on the 2-, 3-, 4-, 6-, and 7-positions of the DHP core led to the identification of compounds potent (EC
50 < 10 nM) against all strains of P. falciparum tested, including the drug-resistant parasite strains K1, W2, and TM90-C2B. Evaluation of efficacy of several compounds in vivo identified two compounds that reduced parasitemia by >75 % in mice 6 days post-exposure following a single 50 mg/kg oral dose. Resistance acquisition experiments with a selected dihydropyridine led to the identification of a single mutation conveying resistance in the gene encoding for Plasmodium falciparum multi-drug resistance protein 1 (PfMDR1). The same dihydropyridine possessed transmission blocking activity. The DHPs have the potential for the development of novel antimalarial drug candidates., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024. Published by Elsevier Masson SAS.)- Published
- 2024
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12. Climate, demography, immunology, and virology combine to drive two decades of dengue virus dynamics in Cambodia.
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Brook CE, Rozins C, Bohl JA, Ahyong V, Chea S, Fahsbender L, Huy R, Lay S, Leang R, Li Y, Lon C, Man S, Oum M, Northrup GR, Oliveira F, Pacheco AR, Parker DM, Young K, Boots M, Tato CM, DeRisi JL, Yek C, and Manning JE
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- Cambodia epidemiology, Humans, Climate, Incidence, Demography, Dengue epidemiology, Dengue virology, Dengue immunology, Dengue transmission, Dengue Virus genetics, Dengue Virus immunology, Phylogeny
- Abstract
The incidence of dengue virus disease has increased globally across the past half-century, with highest number of cases ever reported in 2019 and again in 2023. We analyzed climatological, epidemiological, and phylogenomic data to investigate drivers of two decades of dengue in Cambodia, an understudied endemic setting. Using epidemiological models fit to a 19-y dataset, we first demonstrate that climate-driven transmission alone is insufficient to explain three epidemics across the time series. We then use wavelet decomposition to highlight enhanced annual and multiannual synchronicity in dengue cycles between provinces in epidemic years, suggesting a role for climate in homogenizing dynamics across space and time. Assuming reported cases correspond to symptomatic secondary infections, we next use an age-structured catalytic model to estimate a declining force of infection for dengue through time, which elevates the mean age of reported cases in Cambodia. Reported cases in >70-y-old individuals in the 2019 epidemic are best explained when also allowing for waning multitypic immunity and repeat symptomatic infections in older patients. We support this work with phylogenetic analysis of 192 dengue virus (DENV) genomes that we sequenced between 2019 and 2022, which document emergence of DENV-2 Cosmopolitan Genotype-II into Cambodia. This lineage demonstrates phylogenetic homogeneity across wide geographic areas, consistent with invasion behavior and in contrast to high phylogenetic diversity exhibited by endemic DENV-1. Finally, we simulate an age-structured, mechanistic model of dengue dynamics to demonstrate how expansion of an antigenically distinct lineage that evades preexisting multitypic immunity effectively reproduces the older-age infections witnessed in our data., Competing Interests: Competing interests statement:The authors declare no competing interest.
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- 2024
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13. Anti-RGS8 paraneoplastic cerebellar ataxia is preferentially associated with a particular subtype of Hodgkin's lymphoma.
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Peter E, Ciano-Petersen NL, Do LD, Perrot J, Ngo T, Pluvinage J, Bartley CM, Zorn KC, Miske R, Scharf M, Villagrán-García M, Farina A, Rogemond V, Antoine JC, Tranchant C, Dubois V, DeRisi JL, Pleasure SJ, Wilson MR, Gelfand JM, Traverse-Glehen A, Honnorat J, and Desestret V
- Abstract
Ataxia with anti-regulator of G-protein signaling 8 autoantibodies (RGS8-Abs) is an autoimmune disease recently described in four patients. The present study aimed to identify other patients with RGS8-Abs, describe their clinical features, including the link between RGS8-related autoimmune cerebellar ataxia (ACA) and cancer. Patients with RGS8-Abs were identified retrospectively in the biological collections of the French Reference Center for Paraneoplastic Neurological Syndrome and the University of California San Francisco Center for Encephalitis and Meningitis. Clinical data were collected, and cerebrospinal fluid, serum, and tumor pathological samples were retrieved to characterize the autoantibodies and the associated malignancies. Only three patients with RGS8-Abs were identified. All of them presented with a pure cerebellar ataxia of mild to severe course, unresponsive to current immunotherapy regimens for ACA. Two patients presented with a Hodgkin lymphoma of the rare specific subtype called nodular lymphocyte-predominant Hodgkin lymphoma, with very mild extension. Autoantibodies detected in all patients enriched the same epitope on the RGS8 protein, which is an intracellular protein physiologically expressed in Purkinje cells but also ectopically expressed specifically in lymphoma cells of patients with RGS8-related ACA. The present results and those of the four cases previously described suggest that RGS8-Abs define a new paraneoplastic neurological syndrome of extreme rarity found mostly in middle-aged males that associates pure cerebellar ataxia and a particular lymphoma specifically expressing the RGS8 antigen. As in other paraneoplastic ACA with intracellular antigen, the disease course is severe, and patients tend to exhibit a poor response to immune therapy., (© 2024. The Author(s).)
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- 2024
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14. Molecular mimicry in multisystem inflammatory syndrome in children.
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Bodansky A, Mettelman RC, Sabatino JJ Jr, Vazquez SE, Chou J, Novak T, Moffitt KL, Miller HS, Kung AF, Rackaityte E, Zamecnik CR, Rajan JV, Kortbawi H, Mandel-Brehm C, Mitchell A, Wang CY, Saxena A, Zorn K, Yu DJL, Pogorelyy MV, Awad W, Kirk AM, Asaki J, Pluvinage JV, Wilson MR, Zambrano LD, Campbell AP, Thomas PG, Randolph AG, Anderson MS, and DeRisi JL
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- Child, Humans, Coronavirus Nucleocapsid Proteins chemistry, Coronavirus Nucleocapsid Proteins immunology, Phosphoproteins chemistry, Phosphoproteins immunology, Sorting Nexins chemistry, Sorting Nexins immunology, T-Lymphocytes immunology, Antibodies, Viral immunology, Autoantibodies immunology, COVID-19 immunology, COVID-19 virology, COVID-19 complications, Cross Reactions immunology, Epitopes immunology, Epitopes chemistry, Molecular Mimicry immunology, SARS-CoV-2 chemistry, SARS-CoV-2 immunology, SARS-CoV-2 metabolism, SARS-CoV-2 pathogenicity, Systemic Inflammatory Response Syndrome immunology, Systemic Inflammatory Response Syndrome pathology, Systemic Inflammatory Response Syndrome virology
- Abstract
Multisystem inflammatory syndrome in children (MIS-C) is a severe, post-infectious sequela of SARS-CoV-2 infection
1,2 , yet the pathophysiological mechanism connecting the infection to the broad inflammatory syndrome remains unknown. Here we leveraged a large set of samples from patients with MIS-C to identify a distinct set of host proteins targeted by patient autoantibodies including a particular autoreactive epitope within SNX8, a protein involved in regulating an antiviral pathway associated with MIS-C pathogenesis. In parallel, we also probed antibody responses from patients with MIS-C to the complete SARS-CoV-2 proteome and found enriched reactivity against a distinct domain of the SARS-CoV-2 nucleocapsid protein. The immunogenic regions of the viral nucleocapsid and host SNX8 proteins bear remarkable sequence similarity. Consequently, we found that many children with anti-SNX8 autoantibodies also have cross-reactive T cells engaging both the SNX8 and the SARS-CoV-2 nucleocapsid protein epitopes. Together, these findings suggest that patients with MIS-C develop a characteristic immune response to the SARS-CoV-2 nucleocapsid protein that is associated with cross-reactivity to the self-protein SNX8, demonstrating a mechanistic link between the infection and the inflammatory syndrome, with implications for better understanding a range of post-infectious autoinflammatory diseases., (© 2024. The Author(s).)- Published
- 2024
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15. Phage Immunoprecipitation-Sequencing Reveals CDHR5 Autoantibodies in Select Patients With Interstitial Lung Disease.
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Upadhyay V, Yoon YM, Vazquez SE, Velez TE, Jones KD, Lee CT, Law CS, Wolters PJ, Lee S, Yang MM, Farrand E, Noth I, Strek ME, Anderson MS, DeRisi JL, Sperling AI, and Shum AK
- Abstract
Objective: Interstitial lung diseases (ILDs) are a heterogeneous group of disorders that can develop in patients with connective tissue diseases. Establishing autoimmunity in ILD impacts prognosis and treatment. Patients with ILD are screened for autoimmunity by measuring antinuclear autoantibodies, rheumatoid factors, and other nonspecific tests. However, this approach may miss autoimmunity that manifests as autoantibodies to tissue antigens not previously defined in ILD., Methods: We use Phage Immunoprecipitation-Sequencing (PhIP-Seq) to conduct an autoantibody discovery screen of patients with ILD and controls. We screened for novel autoantigen candidates using PhIP-Seq. We next developed a radio-labeled binding assay and validated the leading candidate in 398 patients with ILD recruited from two academic medical centers and 138 blood bank individuals that formed our reference cohort., Results: PhIP-Seq identified 17 novel autoreactive targets, and machine learning classifiers derived from these targets discriminated ILD serum from controls. Among the 17 candidates, we validated CDHR5 and found CDHR5 autoantibodies in patients with rheumatologic disorders and importantly, patients not previously diagnosed with autoimmunity. Using survival and transplant free-survival data available from one of the two centers, patients with CDHR5 autoantibodies showed worse survival compared with other patients with connective tissue disease ILD., Conclusion: We used PhIP-Seq to define a novel CDHR5 autoantibody in a subset of select patients with ILD. Our data complement a recent study showing polymorphisms in the CDHR5-IRF7 gene locus strongly associated with titer of anticentromere antibodies in systemic sclerosis, creating a growing body of evidence suggesting a link between CDHR5 and autoimmunity., (© 2024 The Author(s). ACR Open Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)
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- 2024
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16. Pathobiological signatures of dysbiotic lung injury in pediatric patients undergoing stem cell transplantation.
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Zinter MS, Dvorak CC, Mayday MY, Reyes G, Simon MR, Pearce EM, Kim H, Shaw PJ, Rowan CM, Auletta JJ, Martin PL, Godder K, Duncan CN, Lalefar NR, Kreml EM, Hume JR, Abdel-Azim H, Hurley C, Cuvelier GDE, Keating AK, Qayed M, Killinger JS, Fitzgerald JC, Hanna R, Mahadeo KM, Quigg TC, Satwani P, Castillo P, Gertz SJ, Moore TB, Hanisch B, Abdel-Mageed A, Phelan R, Davis DB, Hudspeth MP, Yanik GA, Pulsipher MA, Sulaiman I, Segal LN, Versluys BA, Lindemans CA, Boelens JJ, and DeRisi JL
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- Humans, Child, Female, Male, Child, Preschool, Adolescent, Microbiota, Infant, Lung pathology, Lung microbiology, Lung immunology, Lung Injury pathology, Lung Injury microbiology, Hematopoietic Stem Cell Transplantation adverse effects, Bronchoalveolar Lavage Fluid microbiology, Dysbiosis microbiology, Dysbiosis immunology
- Abstract
Hematopoietic cell transplantation (HCT) uses cytotoxic chemotherapy and/or radiation followed by intravenous infusion of stem cells to cure malignancies, bone marrow failure and inborn errors of immunity, hemoglobin and metabolism. Lung injury is a known complication of the process, due in part to disruption in the pulmonary microenvironment by insults such as infection, alloreactive inflammation and cellular toxicity. How microorganisms, immunity and the respiratory epithelium interact to contribute to lung injury is uncertain, limiting the development of prevention and treatment strategies. Here we used 278 bronchoalveolar lavage (BAL) fluid samples to study the lung microenvironment in 229 pediatric patients who have undergone HCT treated at 32 children's hospitals between 2014 and 2022. By leveraging paired microbiome and human gene expression data, we identified high-risk BAL compositions associated with in-hospital mortality (P = 0.007). Disadvantageous profiles included bacterial overgrowth with neutrophilic inflammation, microbiome contraction with epithelial fibroproliferation and profound commensal depletion with viral and staphylococcal enrichment, lymphocytic activation and cellular injury, and were replicated in an independent cohort from the Netherlands (P = 0.022). In addition, a broad array of previously occult pathogens was identified, as well as a strong link between antibiotic exposure, commensal bacterial depletion and enrichment of viruses and fungi. Together these lung-immune system-microorganism interactions clarify the important drivers of fatal lung injury in pediatric patients who have undergone HCT. Further investigation is needed to determine how personalized interpretation of heterogeneous pulmonary microenvironments may be used to improve pediatric HCT outcomes., (© 2024. The Author(s).)
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- 2024
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17. Transcobalamin receptor antibodies in autoimmune vitamin B12 central deficiency.
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Pluvinage JV, Ngo T, Fouassier C, McDonagh M, Holmes BB, Bartley CM, Kondapavulur S, Hurabielle C, Bodansky A, Pai V, Hinman S, Aslanpour A, Alvarenga BD, Zorn KC, Zamecnik C, McCann A, Asencor AI, Huynh T, Browne W, Tubati A, Haney MS, Douglas VC, Louine M, Cree BAC, Hauser SL, Seeley W, Baranzini SE, Wells JA, Spudich S, Farhadian S, Ramachandran PS, Gillum L, Hales CM, Zikherman J, Anderson MS, Yazdany J, Smith B, Nath A, Suh G, Flanagan EP, Green AJ, Green R, Gelfand JM, DeRisi JL, Pleasure SJ, and Wilson MR
- Subjects
- Humans, Female, Receptors, Cell Surface metabolism, Antigens, CD metabolism, Middle Aged, Autoimmune Diseases immunology, Autoimmune Diseases blood, Blood-Brain Barrier metabolism, Male, Vitamin B 12 Deficiency immunology, Vitamin B 12 blood, Autoantibodies blood, Autoantibodies immunology
- Abstract
Vitamin B12 is critical for hematopoiesis and myelination. Deficiency can cause neurologic deficits including loss of coordination and cognitive decline. However, diagnosis relies on measurement of vitamin B12 in the blood, which may not accurately reflect the concentration in the brain. Using programmable phage display, we identified an autoantibody targeting the transcobalamin receptor (CD320) in a patient with progressive tremor, ataxia, and scanning speech. Anti-CD320 impaired cellular uptake of cobalamin (B12) in vitro by depleting its target from the cell surface. Despite a normal serum concentration, B12 was nearly undetectable in her cerebrospinal fluid (CSF). Immunosuppressive treatment and high-dose systemic B12 supplementation were associated with increased B12 in the CSF and clinical improvement. Optofluidic screening enabled isolation of a patient-derived monoclonal antibody that impaired B12 transport across an in vitro model of the blood-brain barrier (BBB). Autoantibodies targeting the same epitope of CD320 were identified in seven other patients with neurologic deficits of unknown etiology, 6% of healthy controls, and 21.4% of a cohort of patients with neuropsychiatric lupus. In 132 paired serum and CSF samples, detection of anti-CD320 in the blood predicted B12 deficiency in the brain. However, these individuals did not display any hematologic signs of B12 deficiency despite systemic CD320 impairment. Using a genome-wide CRISPR screen, we found that the low-density lipoprotein receptor serves as an alternative B12 uptake pathway in hematopoietic cells. These findings dissect the tissue specificity of B12 transport and elucidate an autoimmune neurologic condition that may be amenable to immunomodulatory treatment and nutritional supplementation.
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- 2024
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18. Unveiling the proteome-wide autoreactome enables enhanced evaluation of emerging CAR T cell therapies in autoimmunity.
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Bodansky A, Yu DJ, Rallistan A, Kalaycioglu M, Boonyaratanakornkit J, Green DJ, Gauthier J, Turtle CJ, Zorn K, O'Donovan B, Mandel-Brehm C, Asaki J, Kortbawi H, Kung AF, Rackaityte E, Wang CY, Saxena A, de Dios K, Masi G, Nowak RJ, O'Connor KC, Li H, Diaz VE, Saloner R, Casaletto KB, Gontrum EQ, Chan B, Kramer JH, Wilson MR, Utz PJ, Hill JA, Jackson SW, Anderson MS, and DeRisi JL
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- Humans, Female, Autoimmune Diseases immunology, Autoimmune Diseases therapy, Male, Immunotherapy, Adoptive methods, B-Cell Maturation Antigen immunology, B-Cell Maturation Antigen metabolism, Adult, Receptors, Chimeric Antigen immunology, Receptors, Chimeric Antigen metabolism, Antigens, CD19 immunology, Middle Aged, Proteome, Autoantibodies immunology, Autoimmunity
- Abstract
Given the global surge in autoimmune diseases, it is critical to evaluate emerging therapeutic interventions. Despite numerous new targeted immunomodulatory therapies, comprehensive approaches to apply and evaluate the effects of these treatments longitudinally are lacking. Here, we leveraged advances in programmable-phage immunoprecipitation methodology to explore the modulation, or lack thereof, of autoantibody profiles, proteome-wide, in both health and disease. Using a custom set of over 730,000 human-derived peptides, we demonstrated that each individual, regardless of disease state, possesses a distinct and complex constellation of autoreactive antibodies. For each individual, the set of resulting autoreactivites constituted a unique immunological fingerprint, or "autoreactome," that was remarkably stable over years. Using the autoreactome as a primary output, we evaluated the relative effectiveness of various immunomodulatory therapies in altering autoantibody repertoires. We found that therapies targeting B cell maturation antigen (BCMA) profoundly altered an individual's autoreactome, while anti-CD19 and anti-CD20 therapies had minimal effects. These data both confirm that the autoreactome comprises autoantibodies secreted by plasma cells and strongly suggest that BCMA or other plasma cell-targeting therapies may be highly effective in treating currently refractory autoantibody-mediated diseases.
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- 2024
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19. An autoantibody signature predictive for multiple sclerosis.
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Zamecnik CR, Sowa GM, Abdelhak A, Dandekar R, Bair RD, Wade KJ, Bartley CM, Kizer K, Augusto DG, Tubati A, Gomez R, Fouassier C, Gerungan C, Caspar CM, Alexander J, Wapniarski AE, Loudermilk RP, Eggers EL, Zorn KC, Ananth K, Jabassini N, Mann SA, Ragan NR, Santaniello A, Henry RG, Baranzini SE, Zamvil SS, Sabatino JJ Jr, Bove RM, Guo CY, Gelfand JM, Cuneo R, von Büdingen HC, Oksenberg JR, Cree BAC, Hollenbach JA, Green AJ, Hauser SL, Wallin MT, DeRisi JL, and Wilson MR
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- Humans, Biomarkers blood, Cohort Studies, Female, Male, Adult, Middle Aged, Multiple Sclerosis immunology, Multiple Sclerosis blood, Autoantibodies blood, Autoantibodies immunology, Neurofilament Proteins blood, Neurofilament Proteins immunology
- Abstract
Although B cells are implicated in multiple sclerosis (MS) pathophysiology, a predictive or diagnostic autoantibody remains elusive. In this study, the Department of Defense Serum Repository (DoDSR), a cohort of over 10 million individuals, was used to generate whole-proteome autoantibody profiles of hundreds of patients with MS (PwMS) years before and subsequently after MS onset. This analysis defines a unique cluster in approximately 10% of PwMS who share an autoantibody signature against a common motif that has similarity with many human pathogens. These patients exhibit antibody reactivity years before developing MS symptoms and have higher levels of serum neurofilament light (sNfL) compared to other PwMS. Furthermore, this profile is preserved over time, providing molecular evidence for an immunologically active preclinical period years before clinical onset. This autoantibody reactivity was validated in samples from a separate incident MS cohort in both cerebrospinal fluid and serum, where it is highly specific for patients eventually diagnosed with MS. This signature is a starting point for further immunological characterization of this MS patient subset and may be clinically useful as an antigen-specific biomarker for high-risk patients with clinically or radiologically isolated neuroinflammatory syndromes., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)
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- 2024
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20. Challenges and advances in the medical treatment of granulomatous amebic encephalitis.
- Author
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Spottiswoode N, Haston JC, Hanners NW, Gruenberg K, Kim A, DeRisi JL, and Wilson MR
- Abstract
Granulomatous amebic encephalitis, caused by the free-living amebae Balamuthia mandrillaris or Acanthamoeba species, is a rare and deadly infectious syndrome with a current mortality rate of >90%. Much work remains to define the optimal treatment for these infections. Here, we provide a comprehensive overview of the supporting evidence behind antimicrobials currently recommended by the Centers for Disease Control and Prevention (CDC) with updated statistics on survival rates and medication usage from the CDC Free-Living Ameba Database. We also discuss promising treatments, especially the emerging therapeutic agent nitroxoline, and provide recommendations for the next steps in this area., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2024.)
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- 2024
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21. The antibiotic resistance reservoir of the lung microbiome expands with age in a population of critically ill patients.
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Chu VT, Tsitsiklis A, Mick E, Ambroggio L, Kalantar KL, Glascock A, Osborne CM, Wagner BD, Matthay MA, DeRisi JL, Calfee CS, Mourani PM, and Langelier CR
- Subjects
- Adult, Child, Humans, Critical Illness, Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents therapeutic use, Lung, Drug Resistance, Microbial genetics, Microbiota genetics, Respiratory Tract Infections drug therapy
- Abstract
Antimicrobial resistant lower respiratory tract infections are an increasing public health threat and an important cause of global mortality. The lung microbiome can influence susceptibility of respiratory tract infections and represents an important reservoir for exchange of antimicrobial resistance genes. Studies of the gut microbiome have found an association between age and increasing antimicrobial resistance gene burden, however, corollary studies in the lung microbiome remain absent. We performed an observational study of children and adults with acute respiratory failure admitted to the intensive care unit. From tracheal aspirate RNA sequencing data, we evaluated age-related differences in detectable antimicrobial resistance gene expression in the lung microbiome. Using a multivariable logistic regression model, we find that detection of antimicrobial resistance gene expression was significantly higher in adults compared with children after adjusting for demographic and clinical characteristics. This association remained significant after additionally adjusting for lung bacterial microbiome characteristics, and when modeling age as a continuous variable. The proportion of adults expressing beta-lactam, aminoglycoside, and tetracycline antimicrobial resistance genes was higher compared to children. Together, these findings shape our understanding of the lung resistome in critically ill patients across the lifespan, which may have implications for clinical management and global public health., (© 2024. The Author(s).)
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- 2024
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22. Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNs.
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Bastard P, Vazquez SE, Liu J, Laurie MT, Wang CY, Gervais A, Le Voyer T, Bizien L, Zamecnik C, Philippot Q, Rosain J, Catherinot E, Willmore A, Mitchell AM, Bair R, Garçon P, Kenney H, Fekkar A, Salagianni M, Poulakou G, Siouti E, Sahanic S, Tancevski I, Weiss G, Nagl L, Manry J, Duvlis S, Arroyo-Sánchez D, Paz Artal E, Rubio L, Perani C, Bezzi M, Sottini A, Quaresima V, Roussel L, Vinh DC, Reyes LF, Garzaro M, Hatipoglu N, Boutboul D, Tandjaoui-Lambiotte Y, Borghesi A, Aliberti A, Cassaniti I, Venet F, Monneret G, Halwani R, Sharif-Askari NS, Danielson J, Burrel S, Morbieu C, Stepanovskyy Y, Bondarenko A, Volokha A, Boyarchuk O, Gagro A, Neuville M, Neven B, Keles S, Hernu R, Bal A, Novelli A, Novelli G, Saker K, Ailioaie O, Antolí A, Jeziorski E, Rocamora-Blanch G, Teixeira C, Delaunay C, Lhuillier M, Le Turnier P, Zhang Y, Mahevas M, Pan-Hammarström Q, Abolhassani H, Bompoil T, Dorgham K, Gorochov G, Laouenan C, Rodríguez-Gallego C, Ng LFP, Renia L, Pujol A, Belot A, Raffi F, Allende LM, Martinez-Picado J, Ozcelik T, Imberti L, Notarangelo LD, Troya J, Solanich X, Zhang SY, Puel A, Wilson MR, Trouillet-Assant S, Abel L, Jouanguy E, Ye CJ, Cobat A, Thompson LM, Andreakos E, Zhang Q, Anderson MS, Casanova JL, and DeRisi JL
- Subjects
- Humans, COVID-19 Vaccines, SARS-CoV-2, Vaccination, RNA, Messenger, COVID-19, Vaccines, Interferon Type I
- Abstract
Life-threatening "breakthrough" cases of critical COVID-19 are attributed to poor or waning antibody (Ab) response to SARS-CoV-2 vaccines in individuals already at risk. Preexisting auto-Abs neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; their contribution to hypoxemic breakthrough cases in vaccinated people is unknown. We studied a cohort of 48 individuals (aged 20 to 86 years) who received two doses of a messenger RNA (mRNA) vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Ab levels to the vaccine, neutralization of the virus, and auto-Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal Ab response to the vaccine. Among them, 10 (24%) had auto-Abs neutralizing type I IFNs (aged 43 to 86 years). Eight of these 10 patients had auto-Abs neutralizing both IFN-α2 and IFN-ω, whereas two neutralized IFN-ω only. No patient neutralized IFN-β. Seven neutralized type I IFNs at 10 ng/ml and three at 100 pg/ml only. Seven patients neutralized SARS-CoV-2 D614G and Delta efficiently, whereas one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only type I IFNs at 100 pg/ml neutralized both D614G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating Abs capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a notable proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population.
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- 2023
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23. Unveiling the autoreactome: Proteome-wide immunological fingerprints reveal the promise of plasma cell depleting therapy.
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Bodansky A, Yu DJ, Rallistan A, Kalaycioglu M, Boonyaratanakornkit J, Green DJ, Gauthier J, Turtle CJ, Zorn K, O'Donovan B, Mandel-Brehm C, Asaki J, Kortbawi H, Kung AF, Rackaityte E, Wang CY, Saxena A, de Dios K, Masi G, Nowak RJ, O'Connor KC, Li H, Diaz VE, Casaletto KB, Gontrum EQ, Chan B, Kramer JH, Wilson MR, Utz PJ, Hill JA, Jackson SW, Anderson MS, and DeRisi JL
- Abstract
The prevalence and burden of autoimmune and autoantibody mediated disease is increasing worldwide, yet most disease etiologies remain unclear. Despite numerous new targeted immunomodulatory therapies, comprehensive approaches to apply and evaluate the effects of these treatments longitudinally are lacking. Here, we leverage advances in programmable-phage immunoprecipitation (PhIP-Seq) methodology to explore the modulation, or lack thereof, of proteome-wide autoantibody profiles in both health and disease. We demonstrate that each individual, regardless of disease state, possesses a distinct set of autoreactivities constituting a unique immunological fingerprint, or "autoreactome", that is remarkably stable over years. In addition to uncovering important new biology, the autoreactome can be used to better evaluate the relative effectiveness of various therapies in altering autoantibody repertoires. We find that therapies targeting B-Cell Maturation Antigen (BCMA) profoundly alter an individual's autoreactome, while anti-CD19 and CD-20 therapies have minimal effects, strongly suggesting a rationale for BCMA or other plasma cell targeted therapies in autoantibody mediated diseases., Competing Interests: Competing Interest Declaration Potential Conflicts J.D.R. reports being a founder and paid consultant for Delve Bio, Inc., and a paid consultant for the Public Health Company and Allen & Co. M.A.S. receives unrelated research funding from the NIH, the CDC, Cepheid and Merck and unrelated Honoria from UpToDate, Inc. M.R.W. reports being a founder and paid consultant for Delve Bio, Inc. and receives unrelated research grant funding from Roche/Genentech and Novartis, and received speaking honoraria from Genentech, Takeda, WebMD, and Novartis. C.J.T. reports being on the Scientific Advisory Boards for Caribou Biosciences, T-CURX, Myeloid Therapeutics, ArsenalBio, Cargo Therapeutics, Celgene/BMS Cell Therapy; is a member a DSMB member of Kyverna; is on Ad hoc advisory boards/consulting (last 12 months) for Nektar Therapeutics, Legend Biotech, Prescient Therapeutics, Century Therapeutics, IGM Biosciences, Abbvie; has Stock options in Eureka Therapeutics, Caribou Biosciences, Myeloid Therapeutics, ArsenalBio, Cargo Therapeutics; and reports the right to receive payment from Fred Hutch as an inventor on patents related to CAR T-cell therapy. J.A.H. reports research funding from Merck and Takeda and consulting fees from Takeda, Gilead, SentiBio, and Century Therapeutics. J.G. reports research funding from Sobi, Juno Therapeutics (a BMS company), Celgene (a BMS company), Angiocrine Bioscience; is an Ad hoc consultant for Sobi, Legend Biotech, Janssen, Kite Pharma, MorphoSys. D.J.G. has received research funding, has served as an advisor and has received royalties from Juno Therapeutics, a Bristol-Myers Squibb company; has served as an advisor and received research funding from Seattle Genetics; has served as an advisor for GlaxoSmithKline, Celgene, Janssen Biotech, Ensoma and Legend Biotech; and has received research funding from SpringWorks Therapeutics, Sanofi, and Cellectar Biosciences. K.C.O. received unrelated research funding from, and is an equity shareholder of Cabaletta Bio, and receives unrelated research funding from Seismic, argenx, and Viela Bio/Horizon (now Amgen). R.J.N. reports unrelated research support from the National Institutes of Health, Genentech, Inc., Alexion Pharmaceuticals, Inc., argenx, Annexon Biosciences, Inc., Ra Pharmaceuticals, Inc. (now UCB S.A.), the Myasthenia Gravis Foundation of America, Inc., Momenta Pharmaceuticals, Inc. (now Janssen), Immunovant, Inc., Grifols, S.A., and Viela Bio, Inc. (now Horizon Therapeutics plc). R.J.N. has also served as a consultant/advisor unrelated to research in this manuscript for Alexion Pharmaceuticals, Inc., argenx, Cabaletta Bio, Inc., Cour Pharmaceuticals, CSL Behring, Grifols, S.A., Ra Pharmaceuticals, Inc. (now UCB S.A.), Immunovant, Inc., Momenta Pharmaceuticals, Inc. (now Janssen), and Viela Bio, Inc. (now Horizon Therapeutics plc). J.L.D., C.M.B. and M.R.W. receive licensing fees from CDI Labs.
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- 2023
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24. Validation of a murine proteome-wide phage display library for identification of autoantibody specificities.
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Rackaityte E, Proekt I, Miller HS, Ramesh A, Brooks JF, Kung AF, Mandel-Brehm C, Yu D, Zamecnik CR, Bair R, Vazquez SE, Sunshine S, Abram CL, Lowell CA, Rizzuto G, Wilson MR, Zikherman J, Anderson MS, and DeRisi JL
- Subjects
- Humans, Animals, Mice, Proteome, Autoimmunity, Peptides, Mice, Inbred NOD, Autoantibodies, Bacteriophages
- Abstract
Autoimmunity is characterized by loss of tolerance to tissue-specific as well as systemic antigens, resulting in complex autoantibody landscapes. Here, we introduce and extensively validate the performance characteristics of a murine proteome-wide library for phage display immunoprecipitation and sequencing (PhIP-seq) in profiling mouse autoantibodies. This library was validated using 7 genetically distinct mouse lines across a spectrum of autoreactivity. Mice deficient in antibody production (Rag2-/- and μMT) were used to model nonspecific peptide enrichments, while cross-reactivity was evaluated using anti-ovalbumin B cell receptor-restricted OB1 mice as a proof of principle. The PhIP-seq approach was then utilized to interrogate 3 distinct autoimmune disease models. First, serum from Lyn-/- IgD+/- mice with lupus-like disease was used to identify nuclear and apoptotic bleb reactivities. Second, serum from nonobese diabetic (NOD) mice, a polygenic model of pancreas-specific autoimmunity, was enriched in peptides derived from both insulin and predicted pancreatic proteins. Lastly, Aire-/- mouse sera were used to identify numerous autoantigens, many of which were also observed in previous studies of humans with autoimmune polyendocrinopathy syndrome type 1 carrying recessive mutations in AIRE. These experiments support the use of murine proteome-wide PhIP-seq for antigenic profiling and autoantibody discovery, which may be employed to study a range of immune perturbations in mouse models of autoimmunity profiling.
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- 2023
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25. Whole-genome sequencing rule-out of suspected hospital-onset Rhizopus outbreaks.
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Chu VT, Nafees S, Waltari E, McNeil N, Caughell C, Sanchez-Guerrero E, Wang L, Stanley K, Cunningham G, Wong J, Phelps M, Tato CM, Miller S, DeRisi JL, Yokoe DS, Ramirez-Avila L, and Langelier CR
- Subjects
- Humans, Phylogeny, Hospitals, Disease Outbreaks, Rhizopus genetics, Genome, Bacterial
- Abstract
Two independent temporal-spatial clusters of hospital-onset Rhizopus infections were evaluated using whole-genome sequencing (WGS). Phylogenetic analysis confirmed that isolates within each cluster were unrelated despite epidemiological suspicion of outbreaks. The ITS1 region alone was insufficient for accurate analysis. WGS has utility for rapid rule-out of suspected nosocomial Rhizopus outbreaks.
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- 2023
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26. Detection of High-Risk Paraneoplastic Antibodies against TRIM9 and TRIM67 Proteins.
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Bartley CM, Ngo TT, Do LD, Zekeridou A, Dandekar R, Muñiz-Castrillo S, Alvarenga BD, Zorn KC, Tubati A, Pinto AL, Browne WD, Hullett PW, Terrelonge M, Schubert RD, Piquet AL, Yang B, Montalvo M, Kung AF, Mann SA, Shah MP, Geschwind MD, Gelfand JM, DeRisi JL, Pittock SJ, Honnorat J, Pleasure SJ, and Wilson MR
- Subjects
- Humans, Retrospective Studies, Biomarkers cerebrospinal fluid, Autoantibodies cerebrospinal fluid, Immunoglobulin G, Nerve Tissue Proteins metabolism, Paraneoplastic Cerebellar Degeneration
- Abstract
Objective: Co-occurring anti-tripartite motif-containing protein 9 and 67 autoantibodies (TRIM9/67-IgG) have been reported in only a very few cases of paraneoplastic cerebellar syndrome. The value of these biomarkers and the most sensitive methods of TRIM9/67-IgG detection are not known., Methods: We performed a retrospective, multicenter study to evaluate the cerebrospinal fluid and serum of candidate TRIM9/67-IgG cases by tissue-based immunofluorescence, peptide phage display immunoprecipitation sequencing, overexpression cell-based assay (CBA), and immunoblot. Cases in which TRIM9/67-IgG was detected by at least 2 assays were considered TRIM9/67-IgG positive., Results: Among these cases (n = 13), CBA was the most sensitive (100%) and revealed that all cases had TRIM9 and TRIM67 autoantibodies. Of TRIM9/67-IgG cases with available clinical history, a subacute cerebellar syndrome was the most common presentation (n = 7/10), followed by encephalitis (n = 3/10). Of these 10 patients, 70% had comorbid cancer (7/10), 85% of whom (n = 6/7) had confirmed metastatic disease. All evaluable cancer biopsies expressed TRIM9 protein (n = 5/5), whose expression was elevated in the cancerous regions of the tissue in 4 of 5 cases., Interpretation: TRIM9/67-IgG is a rare but likely high-risk paraneoplastic biomarker for which CBA appears to be the most sensitive diagnostic assay. ANN NEUROL 2023;94:1086-1101., (© 2023 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)
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- 2023
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27. Pulmonary microbiome and transcriptome signatures reveal distinct pathobiologic states associated with mortality in two cohorts of pediatric stem cell transplant patients.
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Zinter MS, Dvorak CC, Mayday MY, Reyes G, Simon MR, Pearce EM, Kim H, Shaw PJ, Rowan CM, Auletta JJ, Martin PL, Godder K, Duncan CN, Lalefar NR, Kreml EM, Hume JR, Abdel-Azim H, Hurley C, Cuvelier GDE, Keating AK, Qayed M, Killinger JS, Fitzgerald JC, Hanna R, Mahadeo KM, Quigg TC, Satwani P, Castillo P, Gertz SJ, Moore TB, Hanisch B, Abdel-Mageed A, Phelan R, Davis DB, Hudspeth MP, Yanik GA, Pulsipher MA, Sulaiman I, Segal LN, Versluys BA, Lindemans CA, Boelens JJ, and DeRisi JL
- Abstract
Lung injury is a major determinant of survival after pediatric hematopoietic cell transplantation (HCT). A deeper understanding of the relationship between pulmonary microbes, immunity, and the lung epithelium is needed to improve outcomes. In this multicenter study, we collected 278 bronchoalveolar lavage (BAL) samples from 229 patients treated at 32 children's hospitals between 2014-2022. Using paired metatranscriptomes and human gene expression data, we identified 4 patient clusters with varying BAL composition. Among those requiring respiratory support prior to sampling, in-hospital mortality varied from 22-60% depending on the cluster (p=0.007). The most common patient subtype, Cluster 1, showed a moderate quantity and high diversity of commensal microbes with robust metabolic activity, low rates of infection, gene expression indicating alveolar macrophage predominance, and low mortality. The second most common cluster showed a very high burden of airway microbes, gene expression enriched for neutrophil signaling, frequent bacterial infections, and moderate mortality. Cluster 3 showed significant depletion of commensal microbes, a loss of biodiversity, gene expression indicative of fibroproliferative pathways, increased viral and fungal pathogens, and high mortality. Finally, Cluster 4 showed profound microbiome depletion with enrichment of Staphylococci and viruses, gene expression driven by lymphocyte activation and cellular injury, and the highest mortality. BAL clusters were modeled with a random forest classifier and reproduced in a geographically distinct validation cohort of 57 patients from The Netherlands, recapitulating similar cluster-based mortality differences (p=0.022). Degree of antibiotic exposure was strongly associated with depletion of BAL microbes and enrichment of fungi. Potential pathogens were parsed from all detected microbes by analyzing each BAL microbe relative to the overall microbiome composition, which yielded increased sensitivity for numerous previously occult pathogens. These findings support personalized interpretation of the pulmonary microenvironment in pediatric HCT, which may facilitate biology-targeted interventions to improve outcomes.
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- 2023
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28. Autoantibodies against type I IFNs in humans with alternative NF-κB pathway deficiency.
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Le Voyer T, Parent AV, Liu X, Cederholm A, Gervais A, Rosain J, Nguyen T, Perez Lorenzo M, Rackaityte E, Rinchai D, Zhang P, Bizien L, Hancioglu G, Ghillani-Dalbin P, Charuel JL, Philippot Q, Gueye MS, Maglorius Renkilaraj MRL, Ogishi M, Soudée C, Migaud M, Rozenberg F, Momenilandi M, Riller Q, Imberti L, Delmonte OM, Müller G, Keller B, Orrego J, Franco Gallego WA, Rubin T, Emiroglu M, Parvaneh N, Eriksson D, Aranda-Guillen M, Berrios DI, Vong L, Katelaris CH, Mustillo P, Raedler J, Bohlen J, Bengi Celik J, Astudillo C, Winter S, McLean C, Guffroy A, DeRisi JL, Yu D, Miller C, Feng Y, Guichard A, Béziat V, Bustamante J, Pan-Hammarström Q, Zhang Y, Rosen LB, Holland SM, Bosticardo M, Kenney H, Castagnoli R, Slade CA, Boztuğ K, Mahlaoui N, Latour S, Abraham RS, Lougaris V, Hauck F, Sediva A, Atschekzei F, Sogkas G, Poli MC, Slatter MA, Palterer B, Keller MD, Pinzon-Charry A, Sullivan A, Droney L, Suan D, Wong M, Kane A, Hu H, Ma C, Grombiříková H, Ciznar P, Dalal I, Aladjidi N, Hie M, Lazaro E, Franco J, Keles S, Malphettes M, Pasquet M, Maccari ME, Meinhardt A, Ikinciogullari A, Shahrooei M, Celmeli F, Frosk P, Goodnow CC, Gray PE, Belot A, Kuehn HS, Rosenzweig SD, Miyara M, Licciardi F, Servettaz A, Barlogis V, Le Guenno G, Herrmann VM, Kuijpers T, Ducoux G, Sarrot-Reynauld F, Schuetz C, Cunningham-Rundles C, Rieux-Laucat F, Tangye SG, Sobacchi C, Doffinger R, Warnatz K, Grimbacher B, Fieschi C, Berteloot L, Bryant VL, Trouillet Assant S, Su H, Neven B, Abel L, Zhang Q, Boisson B, Cobat A, Jouanguy E, Kampe O, Bastard P, Roifman CM, Landegren N, Notarangelo LD, Anderson MS, Casanova JL, and Puel A
- Subjects
- Humans, COVID-19 genetics, COVID-19 immunology, Gain of Function Mutation, Heterozygote, I-kappa B Proteins deficiency, I-kappa B Proteins genetics, Loss of Function Mutation, NF-kappa B p52 Subunit deficiency, NF-kappa B p52 Subunit genetics, Pneumonia, Viral genetics, Pneumonia, Viral immunology, Thymus Gland abnormalities, Thymus Gland immunology, Thymus Gland pathology, Thyroid Epithelial Cells metabolism, Thyroid Epithelial Cells pathology, AIRE Protein, NF-kappaB-Inducing Kinase, Autoantibodies immunology, Genetic Predisposition to Disease, Interferon Type I antagonists & inhibitors, Interferon Type I immunology, NF-kappa B deficiency, NF-kappa B genetics
- Abstract
Patients with autoimmune polyendocrinopathy syndrome type 1 (APS-1) caused by autosomal recessive AIRE deficiency produce autoantibodies that neutralize type I interferons (IFNs)
1,2 , conferring a predisposition to life-threatening COVID-19 pneumonia3 . Here we report that patients with autosomal recessive NIK or RELB deficiency, or a specific type of autosomal-dominant NF-κB2 deficiency, also have neutralizing autoantibodies against type I IFNs and are at higher risk of getting life-threatening COVID-19 pneumonia. In patients with autosomal-dominant NF-κB2 deficiency, these autoantibodies are found only in individuals who are heterozygous for variants associated with both transcription (p52 activity) loss of function (LOF) due to impaired p100 processing to generate p52, and regulatory (IκBδ activity) gain of function (GOF) due to the accumulation of unprocessed p100, therefore increasing the inhibitory activity of IκBδ (hereafter, p52LOF /IκBδGOF ). By contrast, neutralizing autoantibodies against type I IFNs are not found in individuals who are heterozygous for NFKB2 variants causing haploinsufficiency of p100 and p52 (hereafter, p52LOF /IκBδLOF ) or gain-of-function of p52 (hereafter, p52GOF /IκBδLOF ). In contrast to patients with APS-1, patients with disorders of NIK, RELB or NF-κB2 have very few tissue-specific autoantibodies. However, their thymuses have an abnormal structure, with few AIRE-expressing medullary thymic epithelial cells. Human inborn errors of the alternative NF-κB pathway impair the development of AIRE-expressing medullary thymic epithelial cells, thereby underlying the production of autoantibodies against type I IFNs and predisposition to viral diseases., (© 2023. The Author(s).)- Published
- 2023
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29. Systematic functional interrogation of SARS-CoV-2 host factors using Perturb-seq.
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Sunshine S, Puschnik AS, Replogle JM, Laurie MT, Liu J, Zha BS, Nuñez JK, Byrum JR, McMorrow AH, Frieman MB, Winkler J, Qiu X, Rosenberg OS, Leonetti MD, Ye CJ, Weissman JS, DeRisi JL, and Hein MY
- Subjects
- Humans, Proteomics, Lung, Epithelial Cells, SARS-CoV-2 genetics, COVID-19 genetics
- Abstract
Genomic and proteomic screens have identified numerous host factors of SARS-CoV-2, but efficient delineation of their molecular roles during infection remains a challenge. Here we use Perturb-seq, combining genetic perturbations with a single-cell readout, to investigate how inactivation of host factors changes the course of SARS-CoV-2 infection and the host response in human lung epithelial cells. Our high-dimensional data resolve complex phenotypes such as shifts in the stages of infection and modulations of the interferon response. However, only a small percentage of host factors showed such phenotypes upon perturbation. We further identified the NF-κB inhibitor IκBα (NFKBIA), as well as the translation factors EIF4E2 and EIF4H as strong host dependency factors acting early in infection. Overall, our study provides massively parallel functional characterization of host factors of SARS-CoV-2 and quantitatively defines their roles both in virus-infected and bystander cells., (© 2023. Springer Nature Limited.)
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- 2023
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30. The antibiotic resistance reservoir of the lung microbiome expands with age.
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Chu VT, Tsitsiklis A, Mick E, Ambroggio L, Kalantar KL, Glascock A, Osborne CM, Wagner BD, Matthay MA, DeRisi JL, Calfee CS, Mourani PM, and Langelier CR
- Abstract
Antimicrobial resistant lower respiratory tract infections (LRTI) are an increasing public health threat, and an important cause of global mortality. The lung microbiome influences LRTI susceptibility and represents an important reservoir for exchange of antimicrobial resistance genes (ARGs). Studies of the gut microbiome have found an association between age and increasing antimicrobial resistance gene (ARG) burden, however corollary studies in the lung microbiome remain absent, despite the respiratory tract representing one of the most clinically significant sites for drug resistant infections. We performed a prospective, multicenter observational study of 261 children and 88 adults with acute respiratory failure, ranging in age from 31 days to ≥ 89 years, admitted to intensive care units in the United States. We performed RNA sequencing on tracheal aspirates collected within 72 hours of intubation, and evaluated age-related differences in detectable ARG expression in the lung microbiome as a primary outcome. Secondary outcomes included number and classes of ARGs detected, proportion of patients with an ARG class, and composition of the lung microbiome. Multivariable logistic regression models (adults vs children) or continuous age (years) were adjusted for sex, race/ethnicity, LRTI status, and days from intubation to specimen collection. Detection of ARGs was significantly higher in adults compared with children after adjusting for sex, race/ethnicity, LRTI diagnosis, and days from intubation to specimen collection (adjusted odds ratio (aOR): 2.16, 95% confidence interval (CI): 1.10-4.22). A greater proportion of adults compared with children had beta-lactam ARGs (31% (CI: 21-41%) vs 13% (CI: 10-18%)), aminoglycoside ARGs (20% (CI: 13-30%) vs 2% (CI: 0.6-4%)), and tetracycline ARGs (14% (CI: 7-23%) vs 3% (CI: 1-5%)). Adults ≥70 years old had the highest proportion of these three ARG classes. The total bacterial abundance of the lung microbiome increased with age, and microbiome alpha diversity varied with age. Taxonomic composition of the lung microbiome, measured by Bray Curtis dissimilarity index, differed between adults and children (p = 0.003). The association between age and increased ARG detection remained significant after additionally including lung microbiome total bacterial abundance and alpha diversity in the multivariable logistic regression model (aOR: 2.38, (CI: 1.25-4.54)). Furthermore, this association remained robust when modeling age as a continuous variable (aOR: 1.02, (CI: 1.01-1.03) per year of age). Taken together, our results demonstrate that age is an independent risk factor for ARG detection in the lower respiratory tract microbiome. These data shape our understanding of the lung resistome in critically ill patients across the lifespan, which may have implications for clinical management and global public health.
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- 2023
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31. In host evolution of beta lactam resistance during active treatment for Pseudomonas aeruginosa bacteremia.
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Spottiswoode N, Hao S, Sanchez-Guerrero E, Detweiler AM, Mekonen H, Neff N, Macmillan H, Schwartz BS, Engel J, DeRisi JL, Miller SA, and Langelier CR
- Subjects
- United States, Humans, Pseudomonas aeruginosa genetics, beta-Lactam Resistance, Carbapenems, Sepsis, Bacteremia drug therapy
- Abstract
Multidrug-resistant (MDR) Pseudomonas aeruginosa has been declared a serious threat by the United States Centers for Disease Control and Prevention. Here, we used whole genome sequencing (WGS) to investigate recurrent P. aeruginosa bloodstream infections in a severely immunocompromised patient. The infections demonstrated unusual, progressive increases in resistance to beta lactam antibiotics in the setting of active treatment with appropriate, guideline-directed agents. WGS followed by comparative genomic analysis of isolates collected over 44 days demonstrated in host evolution of a single P. aeruginosa isolate characterized by stepwise acquisition of two de-novo genetic resistance mechanisms over the course of treatment. We found a novel deletion affecting the ampC repressor ampD and neighboring gene ampE , which associated with initial cefepime treatment failure. This was followed by acquisition of a porin nonsense mutation, OprD , associated with resistance to carbapenems. This study highlights the potential for in-host evolution of P. aeruginosa during bloodstream infections in severely immunocompromised patients despite appropriate antimicrobial therapy. In addition, it demonstrates the utility of WGS for understanding unusual resistance patterns in the clinical context., Competing Interests: Author SM was employed by the company Illumina, Inc, and by the company Delve Bio, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Spottiswoode, Hao, Sanchez-Guerrero, Detweiler, Mekonen, Neff, Macmillan, Schwartz, Engel, DeRisi, Miller and Langelier.)
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- 2023
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32. Viral co-infection, autoimmunity, and CSF HIV antibody profiles in HIV central nervous system escape.
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Hawes IA, Alvarenga BD, Browne W, Wapniarski A, Dandekar R, Bartley CM, Sowa GM, DeRisi JL, Cinque P, Dravid AN, Pleasure SJ, Gisslen M, Price RW, and Wilson MR
- Subjects
- Humans, Autoimmunity, Case-Control Studies, Herpesvirus 4, Human, Central Nervous System, Autoantigens, Coinfection, Epstein-Barr Virus Infections, HIV Infections cerebrospinal fluid
- Abstract
Antiretroviral therapy (ART) suppresses plasma and cerebrospinal fluid (CSF) HIV replication. Neurosymptomatic (NS) CSF escape is a rare exception in which CNS HIV replication occurs in the setting of neurologic impairment. The origins of NS escape are not fully understood. We performed a case-control study of asymptomatic (AS) escape and NS escape subjects with HIV-negative subjects as controls in which we investigated differential immunoreactivity to self-antigens in the CSF of NS escape by employing neuroanatomic CSF immunostaining and massively multiplexed self-antigen serology (PhIP-Seq). Additionally, we utilized pan-viral serology (VirScan) to deeply profile the CSF anti-viral antibody response and metagenomic next-generation sequencing (mNGS) for pathogen detection. We detected Epstein-Barr virus (EBV) DNA more frequently in the CSF of NS escape subjects than in AS escape subjects. Based on immunostaining and PhIP-Seq, there was evidence for increased immunoreactivity against self-antigens in NS escape CSF. Finally, VirScan revealed several immunodominant epitopes that map to the HIV envelope and gag proteins in the CSF of AS and NS escape subjects. Whether these additional inflammatory markers are byproducts of an HIV-driven process or whether they independently contribute to the neuropathogenesis of NS escape will require further study., Competing Interests: Declaration of Competing Interest Dr. Joseph DeRisi has received grants from the Chan Zuckerberg Biohub, personal fees from the Public Health Company and from Allen & Company; Dr. Michael Wilson has received unrelated grants from Roche/Genentech and Novartis as well as speaking honoraria from Novartis, Takeda, WebMD and Genentech. Drs. Wilson and DeRisi serve as co-founders and advisors for Delve Bio. Dr. Christopher Bartley has received an honorarium for speaking to the Commonwealth Club and owns shares in NowRx Inc. M. Gisslen has received research grants from Gilead Sciences and Janssen-Cilag and honoraria as speaker, DSMB committee member and/or scientific advisor from Amgen, AstraZeneca, Biogen, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline/ViiV, Janssen-Cilag, MSD, Novocure, Novo Nordic, Pfizer and Sanofi, all unrelated to the content of this manuscript., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)
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- 2023
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33. Rubella virus tropism and single-cell responses in human primary tissue and microglia-containing organoids.
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Popova G, Retallack H, Kim CN, Wang A, Shin D, DeRisi JL, and Nowakowski T
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- Pregnancy, Female, Humans, Rubella virus, Microglia, Organoids metabolism, Rubella epidemiology, Rubella metabolism, Neural Stem Cells metabolism
- Abstract
Rubella virus is an important human pathogen that can cause neurological deficits in a developing fetus when contracted during pregnancy. Despite successful vaccination programs in the Americas and many developed countries, rubella remains endemic in many regions worldwide and outbreaks occur wherever population immunity is insufficient. Intense interest since rubella virus was first isolated in 1962 has advanced our understanding of clinical outcomes after infection disrupts key processes of fetal neurodevelopment. Yet it is still largely unknown which cell types in the developing brain are targeted. We show that in human brain slices, rubella virus predominantly infects microglia. This infection occurs in a heterogeneous population but not in a highly microglia-enriched monoculture in the absence of other cell types. By using an organoid-microglia model, we further demonstrate that rubella virus infection leads to a profound interferon response in non-microglial cells, including neurons and neural progenitor cells, and this response is attenuated by the presence of microglia., Competing Interests: GP, HR, CK, AW, DS, JD, TN No competing interests declared, (© 2023, Popova, Retallack et al.)
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- 2023
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34. Autoantigen profiling reveals a shared post-COVID signature in fully recovered and long COVID patients.
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Bodansky A, Wang CY, Saxena A, Mitchell A, Kung AF, Takahashi S, Anglin K, Huang B, Hoh R, Lu S, Goldberg SA, Romero J, Tran B, Kirtikar R, Grebe H, So M, Greenhouse B, Durstenfeld MS, Hsue PY, Hellmuth J, Kelly JD, Martin JN, Anderson MS, Deeks SG, Henrich TJ, DeRisi JL, and Peluso MJ
- Subjects
- Humans, SARS-CoV-2, Autoantibodies, Autoantigens, Post-Acute COVID-19 Syndrome, COVID-19
- Abstract
Some individuals do not return to baseline health following SARS-CoV-2 infection, leading to a condition known as long COVID. The underlying pathophysiology of long COVID remains unknown. Given that autoantibodies have been found to play a role in severity of SARS-CoV-2 infection and certain other post-COVID sequelae, their potential role in long COVID is important to investigate. Here, we apply a well-established, unbiased, proteome-wide autoantibody detection technology (T7 phage-display assay with immunoprecipitation and next-generation sequencing, PhIP-Seq) to a robustly phenotyped cohort of 121 individuals with long COVID, 64 individuals with prior COVID-19 who reported full recovery, and 57 pre-COVID controls. While a distinct autoreactive signature was detected that separated individuals with prior SARS-CoV-2 infection from those never exposed to SARS-CoV-2, we did not detect patterns of autoreactivity that separated individuals with long COVID from individuals fully recovered from COVID-19. These data suggest that there are robust alterations in autoreactive antibody profiles due to infection; however, no association of autoreactive antibodies and long COVID was apparent by this assay.
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- 2023
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35. A Predictive Autoantibody Signature in Multiple Sclerosis.
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Zamecnik CR, Sowa GM, Abdelhak A, Dandekar R, Bair RD, Wade KJ, Bartley CM, Tubati A, Gomez R, Fouassier C, Gerungan C, Alexander J, Wapniarski AE, Loudermilk RP, Eggers EL, Zorn KC, Ananth K, Jabassini N, Mann SA, Ragan NR, Santaniello A, Henry RG, Baranzini SE, Zamvil SS, Bove RM, Guo CY, Gelfand JM, Cuneo R, von Büdingen HC, Oksenberg JR, Cree BA, Hollenbach JA, Green AJ, Hauser SL, Wallin MT, DeRisi JL, and Wilson MR
- Abstract
Although B cells are implicated in multiple sclerosis (MS) pathophysiology, a predictive or diagnostic autoantibody remains elusive. Here, the Department of Defense Serum Repository (DoDSR), a cohort of over 10 million individuals, was used to generate whole-proteome autoantibody profiles of hundreds of patients with MS (PwMS) years before and subsequently after MS onset. This analysis defines a unique cluster of PwMS that share an autoantibody signature against a common motif that has similarity with many human pathogens. These patients exhibit antibody reactivity years before developing MS symptoms and have higher levels of serum neurofilament light (sNfL) compared to other PwMS. Furthermore, this profile is preserved over time, providing molecular evidence for an immunologically active prodromal period years before clinical onset. This autoantibody reactivity was validated in samples from a separate incident MS cohort in both cerebrospinal fluid (CSF) and serum, where it is highly specific for patients eventually diagnosed with MS. This signature is a starting point for further immunological characterization of this MS patient subset and may be clinically useful as an antigen-specific biomarker for high-risk patients with clinically- or radiologically-isolated neuroinflammatory syndromes.
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- 2023
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36. Antigenic responses are hallmarks of fibrotic interstitial lung diseases independent of underlying etiologies.
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Yoon YM, Velez TE, Upadhyay V, Vazquez SE, Lee CT, Selvan KC, Law CS, Blaine KM, Hollinger MK, Decker DC, Clark MR, Strek ME, Guzy RD, Adegunsoye A, Noth I, Wolters PJ, Anderson M, DeRisi JL, Shum AK, and Sperling AI
- Abstract
Interstitial lung diseases (ILD) are heterogeneous conditions that may lead to progressive fibrosis and death of affected individuals. Despite diversity in clinical manifestations, enlargement of lung-associated lymph nodes (LLN) in fibrotic ILD patients predicts worse survival. Herein, we revealed a common adaptive immune landscape in LLNs of all ILD patients, characterized by highly activated germinal centers and antigen-activated T cells including regulatory T cells (Tregs). In support of these findings, we identified serum reactivity to 17 candidate auto-antigens in ILD patients through a proteome-wide screening using phage immunoprecipitation sequencing. Autoantibody responses to actin binding LIM protein 1 (ABLIM1), a protein highly expressed in aberrant basaloid cells of fibrotic lungs, were correlated with LLN frequencies of T follicular helper cells and Tregs in ILD patients. Together, we demonstrate that end-stage ILD patients have converging immune mechanisms, in part driven by antigen-specific immune responses, which may contribute to disease progression., Competing Interests: Conflicts of Interest M.E. Strek received grants from editorial assistance from Boehringer Ingelheim and personal fees from Fibrogen. A. Adegunsoye received grants and personal fees from Boehringer Ingelheim, Roche, Inogen, and Medscape. P. J. Wolters received grants from Roche, Sanofi, Pliant, Boehringer Ingelheim, and personal fees from Sanofi, Boehringer Ingelheim, and Blade Therapeutics. M. Anderson owns stock in Medtronic and Merck and has consulted for Sana and Imcyse. J.L. Derisi is a paid scientific consultant for The Public Health Company, Inc., Allen & Co., and Delve Bio. There is no direct overlap between the current study and these consulting duties. These authors have no additional financial interests. The other authors have no conflicting financial interests.
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- 2023
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37. Validation of a murine proteome-wide phage display library for the identification of autoantibody specificities.
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Rackaityte E, Proekt I, Miller HS, Ramesh A, Brooks JF, Kung AF, Mandel-Brehm C, Yu D, Zamecnik C, Bair R, Vazquez SE, Sunshine S, Abram CL, Lowell CA, Rizzuto G, Wilson MR, Zikherman J, Anderson MS, and DeRisi JL
- Abstract
Autoimmunity is characterized by loss of tolerance to tissue-specific as well as systemic antigens, resulting in complex autoantibody landscapes. Here, we introduce and extensively validate the performance characteristics of a murine proteome-wide library for phage display immunoprecipitation and sequencing (PhIP-seq), to profile mouse autoantibodies. This system and library were validated using seven genetic mouse models across a spectrum of autoreactivity. Mice deficient in antibody production ( Rag2
-/- and μMT) were used to model non-specific peptide enrichments, while cross-reactivity was evaluated using anti-ovalbumin B cell receptor (BCR)-restricted OB1 mice as a proof of principle. The PhIP-seq approach was then utilized to interrogate three distinct autoimmune disease models. First, serum from Lyn-/- IgD+/- mice with lupus-like disease was used to identify nuclear and apoptotic bleb reactivities, lending support to the hypothesis that apoptosis is a shared origin of these antigens. Second, serum from non-obese diabetic (NOD) mice, a polygenic model of pancreas-specific autoimmunity, enriched peptides derived from both insulin and predicted pancreatic proteins. Lastly, Aire-/- mouse sera were used to identify numerous auto-antigens, many of which were also observed in previous studies of humans with autoimmune polyendocrinopathy syndrome type 1 (APS1) carrying recessive mutations in AIRE. Among these were peptides derived from Perilipin-1, a validated autoimmune biomarker of generalized acquired lipodystrophy in humans. Autoreactivity to Perilipin-1 correlated with lymphocyte infiltration in adipose tissue and underscores the approach in revealing previously unknown specificities. These experiments support the use of murine proteome-wide PhIP-seq for antigenic profiling and autoantibody discovery, which may be employed to study a range of immune perturbations in mouse models of autoimmunity., Competing Interests: No potential conflicts of interest relevant to this article were reported.- Published
- 2023
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38. Integrated host/microbe metagenomics enables accurate lower respiratory tract infection diagnosis in critically ill children.
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Mick E, Tsitsiklis A, Kamm J, Kalantar KL, Caldera S, Lyden A, Tan M, Detweiler AM, Neff N, Osborne CM, Williamson KM, Soesanto V, Leroue M, Maddux AB, Simões EA, Carpenter TC, Wagner BD, DeRisi JL, Ambroggio L, Mourani PM, and Langelier CR
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- Humans, Child, Metagenomics, Critical Illness, Lung, Respiratory Tract Infections diagnosis, Respiratory Tract Infections microbiology, Microbiota
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BACKGROUNDLower respiratory tract infection (LRTI) is a leading cause of death in children worldwide. LRTI diagnosis is challenging because noninfectious respiratory illnesses appear clinically similar and because existing microbiologic tests are often falsely negative or detect incidentally carried microbes, resulting in antimicrobial overuse and adverse outcomes. Lower airway metagenomics has the potential to detect host and microbial signatures of LRTI. Whether it can be applied at scale and in a pediatric population to enable improved diagnosis and treatment remains unclear.METHODSWe used tracheal aspirate RNA-Seq to profile host gene expression and respiratory microbiota in 261 children with acute respiratory failure. We developed a gene expression classifier for LRTI by training on patients with an established diagnosis of LRTI (n = 117) or of noninfectious respiratory failure (n = 50). We then developed a classifier that integrates the host LRTI probability, abundance of respiratory viruses, and dominance in the lung microbiome of bacteria/fungi considered pathogenic by a rules-based algorithm.RESULTSThe host classifier achieved a median AUC of 0.967 by cross-validation, driven by activation markers of T cells, alveolar macrophages, and the interferon response. The integrated classifier achieved a median AUC of 0.986 and increased the confidence of patient classifications. When applied to patients with an uncertain diagnosis (n = 94), the integrated classifier indicated LRTI in 52% of cases and nominated likely causal pathogens in 98% of those.CONCLUSIONLower airway metagenomics enables accurate LRTI diagnosis and pathogen identification in a heterogeneous cohort of critically ill children through integration of host, pathogen, and microbiome features.FUNDINGSupport for this study was provided by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Heart, Lung, and Blood Institute (UG1HD083171, 1R01HL124103, UG1HD049983, UG01HD049934, UG1HD083170, UG1HD050096, UG1HD63108, UG1HD083116, UG1HD083166, UG1HD049981, K23HL138461, and 5R01HL155418) as well as by the Chan Zuckerberg Biohub.
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- 2023
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39. Genomic analysis, immunomodulation and deep phenotyping of patients with nodding syndrome.
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Soldatos A, Nutman TB, Johnson T, Dowell SF, Sejvar JJ, Wilson MR, DeRisi JL, Inati SK, Groden C, Evans C, O'Connell EM, Toliva BO, Aceng JR, Aryek-Kwe J, Toro C, Stratakis CA, Buckler AG, Cantilena C, Palmore TN, Thurm A, Baker EH, Chang R, Fauni H, Adams D, Macnamara EF, Lau CC, Malicdan MCV, Pusey-Swerdzewski B, Downing R, Bunga S, Thomas JD, Gahl WA, and Nath A
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- United States, Humans, Cohort Studies, Immunomodulation, Genomics, Nodding Syndrome, Onchocerciasis
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The aetiology of nodding syndrome remains unclear, and comprehensive genotyping and phenotyping data from patients remain sparse. Our objectives were to characterize the phenotype of patients with nodding syndrome, investigate potential contributors to disease aetiology, and evaluate response to immunotherapy. This cohort study investigated members of a single-family unit from Lamwo District, Uganda. The participants for this study were selected by the Ugandan Ministry of Health as representative for nodding syndrome and with a conducive family structure for genomic analyses. Of the eight family members who participated in the study at the National Institutes of Health (NIH) Clinical Center, three had nodding syndrome. The three affected patients were extensively evaluated with metagenomic sequencing for infectious pathogens, exome sequencing, spinal fluid immune analyses, neurometabolic and toxicology testing, continuous electroencephalography and neuroimaging. Five unaffected family members underwent a subset of testing for comparison. A distinctive interictal pattern of sleep-activated bursts of generalized and multifocal epileptiform discharges and slowing was observed in two patients. Brain imaging showed two patients had mild generalized cerebral atrophy, and both patients and unaffected family members had excessive metal deposition in the basal ganglia. Trace metal biochemical evaluation was normal. CSF was non-inflammatory and one patient had CSF-restricted oligoclonal bands. Onchocerca volvulus-specific antibodies were present in all patients and skin snips were negative for active onchocerciasis. Metagenomic sequencing of serum and CSF revealed hepatitis B virus in the serum of one patient. Vitamin B6 metabolites were borderline low in all family members and CSF pyridoxine metabolites were normal. Mitochondrial DNA testing was normal. Exome sequencing did not identify potentially causal candidate gene variants. Nodding syndrome is characterized by a distinctive pattern of sleep-activated epileptiform activity. The associated growth stunting may be due to hypothalamic dysfunction. Extensive testing years after disease onset did not clarify a causal aetiology. A trial of immunomodulation (plasmapheresis in two patients and intravenous immunoglobulin in one patient) was given without short-term effect, but longer-term follow-up was not possible to fully assess any benefit of this intervention., (Published by Oxford University Press on behalf of the Guarantors of Brain 2022.)
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- 2023
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40. A 2-Gene Host Signature for Improved Accuracy of COVID-19 Diagnosis Agnostic to Viral Variants.
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Albright J, Mick E, Sanchez-Guerrero E, Kamm J, Mitchell A, Detweiler AM, Neff N, Tsitsiklis A, Hayakawa Serpa P, Ratnasiri K, Havlir D, Kistler A, DeRisi JL, Pisco AO, and Langelier CR
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- Humans, SARS-CoV-2 genetics, COVID-19 Testing, Pandemics, Sensitivity and Specificity, COVID-19 diagnosis
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The continued emergence of SARS-CoV-2 variants is one of several factors that may cause false-negative viral PCR test results. Such tests are also susceptible to false-positive results due to trace contamination from high viral titer samples. Host immune response markers provide an orthogonal indication of infection that can mitigate these concerns when combined with direct viral detection. Here, we leverage nasopharyngeal swab RNA-seq data from patients with COVID-19, other viral acute respiratory illnesses, and nonviral conditions ( n = 318) to develop support vector machine classifiers that rely on a parsimonious 2-gene host signature to diagnose COVID-19. We find that optimal classifiers include an interferon-stimulated gene that is strongly induced in COVID-19 compared with nonviral conditions, such as IFI6 , and a second immune-response gene that is more strongly induced in other viral infections, such as GBP5 . The IFI6 + GBP5 classifier achieves an area under the receiver operating characteristic curve (AUC) greater than 0.9 when evaluated on an independent RNA-seq cohort ( n = 553). We further provide proof-of-concept demonstration that the classifier can be implemented in a clinically relevant RT-qPCR assay. Finally, we show that its performance is robust across common SARS-CoV-2 variants and is unaffected by cross-contamination, demonstrating its utility for improved accuracy of COVID-19 diagnostics. IMPORTANCE In this work, we study upper respiratory tract gene expression to develop and validate a 2-gene host-based COVID-19 diagnostic classifier and then demonstrate its implementation in a clinically practical qPCR assay. We find that the host classifier has utility for mitigating false-negative results, for example due to SARS-CoV-2 variants harboring mutations at primer target sites, and for mitigating false-positive viral PCR results due to laboratory cross-contamination. Both types of error carry serious consequences of either unrecognized viral transmission or unnecessary isolation and contact tracing. This work is directly relevant to the ongoing COVID-19 pandemic given the continued emergence of viral variants and the continued challenges of false-positive PCR assays. It also suggests the feasibility of pan-respiratory virus host-based diagnostics that would have value in congregate settings, such as hospitals and nursing homes, where unrecognized respiratory viral transmission is of particular concern.
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- 2023
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41. Antibodies to repeat-containing antigens in Plasmodium falciparum are exposure-dependent and short-lived in children in natural malaria infections.
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Raghavan M, Kalantar KL, Duarte E, Teyssier N, Takahashi S, Kung AF, Rajan JV, Rek J, Tetteh KKA, Drakeley C, Ssewanyana I, Rodriguez-Barraquer I, Greenhouse B, and DeRisi JL
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- Adult, Humans, Child, Plasmodium falciparum, Antigens, Protozoan, Antibodies, Protozoan, Epitopes, Protozoan Proteins, Malaria, Malaria, Falciparum
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Protection against Plasmodium falciparum , which is primarily antibody-mediated, requires recurrent exposure to develop. The study of both naturally acquired limited immunity and vaccine induced protection against malaria remains critical for ongoing eradication efforts. Towards this goal, we deployed a customized P. falciparum PhIP-seq T7 phage display library containing 238,068 tiled 62-amino acid peptides, covering all known coding regions, including antigenic variants, to systematically profile antibody targets in 198 Ugandan children and adults from high and moderate transmission settings. Repeat elements - short amino acid sequences repeated within a protein - were significantly enriched in antibody targets. While breadth of responses to repeat-containing peptides was twofold higher in children living in the high versus moderate exposure setting, no such differences were observed for peptides without repeats, suggesting that antibody responses to repeat-containing regions may be more exposure dependent and/or less durable in children than responses to regions without repeats. Additionally, short motifs associated with seroreactivity were extensively shared among hundreds of antigens, potentially representing cross-reactive epitopes. PfEMP1 shared motifs with the greatest number of other antigens, partly driven by the diversity of PfEMP1 sequences. These data suggest that the large number of repeat elements and potential cross-reactive epitopes found within antigenic regions of P. falciparum could contribute to the inefficient nature of malaria immunity., Competing Interests: MR, KK, ED, NT, ST, AK, JR, JR, KT, CD, IS, BG No competing interests declared, IR Reviewing editor, eLife, JD Paid scientific advisor for Allen & Co. Paid scientific advisor for the Public Health Company, Inc and holds stock options. Founder and holding stock options in VeriPhi Health, Inc, (© 2023, Raghavan et al.)
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- 2023
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42. Dual ankyrinG and subpial autoantibodies in a man with well-controlled HIV infection with steroid-responsive meningoencephalitis: A case report.
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Bartley CM, Ngo TT, Cadwell CR, Harroud A, Schubert RD, Alvarenga BD, Hawes IA, Zorn KC, Hunyh T, Teliska LH, Kung AF, Shah S, Gelfand JM, Chow FC, Rasband MN, Dubey D, Pittock SJ, DeRisi JL, Wilson MR, and Pleasure SJ
- Abstract
Neuroinvasive infection is the most common cause of meningoencephalitis in people living with human immunodeficiency virus (HIV), but autoimmune etiologies have been reported. We present the case of a 51-year-old man living with HIV infection with steroid-responsive meningoencephalitis whose comprehensive pathogen testing was non-diagnostic. Subsequent tissue-based immunofluorescence with acute-phase cerebrospinal fluid revealed anti-neural antibodies localizing to the axon initial segment (AIS), the node of Ranvier (NoR), and the subpial space. Phage display immunoprecipitation sequencing identified ankyrinG (AnkG) as the leading candidate autoantigen. A synthetic blocking peptide encoding the PhIP-Seq-identified AnkG epitope neutralized CSF IgG binding to the AIS and NoR, thereby confirming a monoepitopic AnkG antibody response. However, subpial immunostaining persisted, indicating the presence of additional autoantibodies. Review of archival tissue-based staining identified candidate AnkG autoantibodies in a 60-year-old woman with metastatic ovarian cancer and seizures that were subsequently validated by cell-based assay. AnkG antibodies were not detected by tissue-based assay and/or PhIP-Seq in control CSF ( N = 39), HIV CSF ( N = 79), or other suspected and confirmed neuroinflammatory CSF cases ( N = 1,236). Therefore, AnkG autoantibodies in CSF are rare but extend the catalog of AIS and NoR autoantibodies associated with neurological autoimmunity., Competing Interests: CB owns shares in NowRx Inc. JG has received unrelated clinical trial support through UCSF from Roche/Genentech and Vigil Neurosciences, personal fees for consulting from Biogen, and personal fees for medical-legal consulting. FC has received personal fees for medical-legal consulting. SS has received personal compensation for serving on medical advisory boards for Alexion Pharmaceuticals, and Horizon Therapeutics. DD has patents pending for KLHL11-IgG, LUZP4-IgG, and cavin-4-IgG as markers of neurological autoimmunity. DD has also received funding from the US Department of Defense (DOD) (CA210208). DD has consulted for UCB, Immunovant, Argenx, and Astellas. All compensation for consulting activities is paid directly to Mayo Clinic. SeP has received personal compensation for serving as a consultant for Genentech, Sage Therapeutics, and Astellas. He's received personal compensation for serving on scientific advisory boards or data safety monitoring boards for F. Hoffman-LaRoche AG, Genentech, and UCB. His institution has received compensation for serving as a consultant for Astellas, Alexion, and Viela Bio/MedImmune. All compensation is paid to Mayo Clinic. He has received research support from Alexion, Viela Bio/MedImmune, Roche/Genentech. He has a patent, Patent# 8,889,102 (Application#12-678350, Neuromyelitis Optica Autoantibodies as a Marker for Neoplasia)—issued; a patent, Patent# 9,891,219B2 (Application#12-573942, Methods for Treating Neuromyelitis Optica (NMO) by Administration of Eculizumab to an individual that is Aquaporin-4 (AQP4)-IgG Autoantibody positive)—issued. JD has received grants from the Chan Zuckerberg Biohub, personal fees from the Public Health Company and from Allen & Company. MW has received unrelated grants from Roche/Genentech and Novartis as well as speaking honoraria from Novartis, Takeda, WebMD and Genentech. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Bartley, Ngo, Cadwell, Harroud, Schubert, Alvarenga, Hawes, Zorn, Hunyh, Teliska, Kung, Shah, Gelfand, Chow, Rasband, Dubey, Pittock, DeRisi, Wilson and Pleasure.)
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- 2023
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43. Low Prevalence of Interferon α Autoantibodies in People Experiencing Symptoms of Post-Coronavirus Disease 2019 (COVID-19) Conditions, or Long COVID.
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Peluso MJ, Mitchell A, Wang CY, Takahashi S, Hoh R, Tai V, Durstenfeld MS, Hsue PY, Kelly JD, Martin JN, Wilson MR, Greenhouse B, Deeks SG, DeRisi JL, and Henrich TJ
- Subjects
- Humans, SARS-CoV-2, Interferon-alpha, Post-Acute COVID-19 Syndrome, Autoantibodies, Prevalence, COVID-19
- Abstract
Interferon (IFN)-specific autoantibodies have been implicated in severe coronavirus disease 2019 (COVID-19) and have been proposed as a potential driver of the persistent symptoms characterizing "long COVID," a type of postacute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We report that only 2 of 215 participants with convalescent SARS-CoV-2 infection tested over 394 time points, including 121 people experiencing long COVID symptoms, had detectable IFN-α2 antibodies. Both had been hospitalized during the acute phase of the infection. These data suggest that persistent anti-IFN antibodies, although a potential driver of severe COVID-19, are unlikely to contribute to long COVID symptoms in the postacute phase of the infection., Competing Interests: Potential conflicts of interest. T. J. H. reports grants from Merck, Gilead Biosciences, and Bristol-Myers Squibb, outside the submitted work. T. J. H. has provided consulting for Roche. S. G. D. reports grants and/or personal fees from Gilead Sciences, Merck, ViiV, AbbVie, Eli Lilly, ByroLogyx, and Enochian Biosciences, outside the submitted work. JD reports paid compensation for consulting for the Public Health Company and Allen & Co. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2023
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44. Prolonged silent carriage, genomic virulence potential and transmission between staff and patients characterize a neonatal intensive care unit (NICU) outbreak of methicillin-resistant Staphylococcus aureus (MRSA).
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Madera S, McNeil N, Serpa PH, Kamm J, Pak C, Caughell C, Nichols A, Dynerman D, Li LM, Sanchez-Guerrero E, Phelps MS, Detweiler AM, Neff N, Reyes H, Miller SA, Yokoe DS, DeRisi JL, Ramirez-Avila L, and Langelier CR
- Subjects
- Infant, Newborn, Infant, Humans, Intensive Care Units, Neonatal, Virulence genetics, Prospective Studies, Phylogeny, Disease Outbreaks prevention & control, Infection Control methods, Genomics, Methicillin-Resistant Staphylococcus aureus genetics, Cross Infection epidemiology, Staphylococcal Infections prevention & control
- Abstract
Background: Methicillin-resistant Staphylococcus aureus (MRSA) is an important pathogen in neonatal intensive care units (NICU) that confers significant morbidity and mortality., Objective: Improving our understanding of MRSA transmission dynamics, especially among high-risk patients, is an infection prevention priority., Methods: We investigated a cluster of clinical MRSA cases in the NICU using a combination of epidemiologic review and whole-genome sequencing (WGS) of isolates from clinical and surveillance cultures obtained from patients and healthcare personnel (HCP)., Results: Phylogenetic analysis identified 2 genetically distinct phylogenetic clades and revealed multiple silent-transmission events between HCP and infants. The predominant outbreak strain harbored multiple virulence factors. Epidemiologic investigation and genomic analysis identified a HCP colonized with the dominant MRSA outbreak strain who cared for most NICU patients who were infected or colonized with the same strain, including 1 NICU patient with severe infection 7 months before the described outbreak. These results guided implementation of infection prevention interventions that prevented further transmission events., Conclusions: Silent transmission of MRSA between HCP and NICU patients likely contributed to a NICU outbreak involving a virulent MRSA strain. WGS enabled data-driven decision making to inform implementation of infection control policies that mitigated the outbreak. Prospective WGS coupled with epidemiologic analysis can be used to detect transmission events and prompt early implementation of control strategies.
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- 2023
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45. Autoantibodies to Perilipin-1 Define a Subset of Acquired Generalized Lipodystrophy.
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Mandel-Brehm C, Vazquez SE, Liverman C, Cheng M, Quandt Z, Kung AF, Parent A, Miao B, Disse E, Cugnet-Anceau C, Dalle S, Orlova E, Frolova E, Alba D, Michels A, Oftedal BE, Lionakis MS, Husebye ES, Agarwal AK, Li X, Zhu C, Li Q, Oral E, Brown R, Anderson MS, Garg A, and DeRisi JL
- Subjects
- Humans, Animals, Mice, Perilipin-1 metabolism, Autoantibodies, Adipose Tissue metabolism, Lipodystrophy, Congenital Generalized metabolism, Lipodystrophy, Congenital Generalized pathology, Lipodystrophy metabolism
- Abstract
Acquired lipodystrophy is often characterized as an idiopathic subtype of lipodystrophy. Despite suspicion of an immune-mediated pathology, biomarkers such as autoantibodies are generally lacking. Here, we used an unbiased proteome-wide screening approach to identify autoantibodies to the adipocyte-specific lipid droplet protein perilipin 1 (PLIN1) in a murine model of autoimmune polyendocrine syndrome type 1 (APS1). We then tested for PLIN1 autoantibodies in human subjects with acquired lipodystrophy with two independent severe breaks in immune tolerance (including APS1) along with control subjects using a specific radioligand binding assay and indirect immunofluorescence on fat tissue. We identified autoantibodies to PLIN1 in these two cases, including the first reported case of APS1 with acquired lipodystrophy and a second patient who acquired lipodystrophy as an immune-related adverse event following cancer immunotherapy. Lastly, we also found PLIN1 autoantibodies to be specifically enriched in a subset of patients with acquired generalized lipodystrophy (17 of 46 [37%]), particularly those with panniculitis and other features of autoimmunity. These data lend additional support to new literature that suggests that PLIN1 autoantibodies represent a marker of acquired autoimmune lipodystrophies and further link them to a break in immune tolerance., (© 2022 by the American Diabetes Association.)
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- 2023
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46. Successful Treatment of Balamuthia mandrillaris Granulomatous Amebic Encephalitis with Nitroxoline.
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Spottiswoode N, Pet D, Kim A, Gruenberg K, Shah M, Ramachandran A, Laurie MT, Zia M, Fouassier C, Boutros CL, Lu R, Zhang Y, Servellita V, Bollen A, Chiu CY, Wilson MR, Valdivia L, and DeRisi JL
- Subjects
- Humans, Granuloma, Brain, Balamuthia mandrillaris, Amebiasis drug therapy, Infectious Encephalitis
- Abstract
A patient in California, USA, with rare and usually fatal Balamuthia mandrillaris granulomatous amebic encephalitis survived after receiving treatment with a regimen that included the repurposed drug nitroxoline. Nitroxoline, which is a quinolone typically used to treat urinary tract infections, was identified in a screen for drugs with amebicidal activity against Balamuthia.
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- 2023
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47. Prevalence of type-1 interferon autoantibodies in adults with non-COVID-19 acute respiratory failure.
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Ghale R, Spottiswoode N, Anderson MS, Mitchell A, Wang G, Calfee CS, DeRisi JL, and Langelier CR
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- Humans, Adult, Autoantibodies, Prevalence, Prospective Studies, COVID-19, Interferon Type I, Respiratory Distress Syndrome, Respiratory Insufficiency diagnosis, Respiratory Insufficiency epidemiology
- Abstract
Auto-antibodies (Abs) to type I interferons (IFNs) are found in up to 25% of patients with severe COVID-19, and are implicated in disease pathogenesis. It has remained unknown, however, whether type I IFN auto-Abs are unique to COVID-19, or are also found in other types of severe respiratory illnesses. To address this, we studied a prospective cohort of 284 adults with acute respiratory failure due to causes other than COVID-19. We measured type I IFN auto-Abs by radio ligand binding assay and screened for respiratory viruses using clinical PCR and metagenomic sequencing. Three patients (1.1%) tested positive for type I IFN auto-Abs, and each had a different underlying clinical presentation. Of the 35 patients found to have viral infections, only one patient tested positive for type I IFN auto-Abs. Together, our data suggest that type I IFN auto-Abs are uncommon in critically ill patients with acute respiratory failure due to causes other than COVID-19., (© 2022. The Author(s).)
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- 2022
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48. Integrated host-microbe plasma metagenomics for sepsis diagnosis in a prospective cohort of critically ill adults.
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Kalantar KL, Neyton L, Abdelghany M, Mick E, Jauregui A, Caldera S, Serpa PH, Ghale R, Albright J, Sarma A, Tsitsiklis A, Leligdowicz A, Christenson SA, Liu K, Kangelaris KN, Hendrickson C, Sinha P, Gomez A, Neff N, Pisco A, Doernberg SB, Derisi JL, Matthay MA, Calfee CS, and Langelier CR
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- Adult, Humans, Prospective Studies, Cohort Studies, RNA, Critical Illness, Sepsis diagnosis
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We carried out integrated host and pathogen metagenomic RNA and DNA next generation sequencing (mNGS) of whole blood (n = 221) and plasma (n = 138) from critically ill patients following hospital admission. We assigned patients into sepsis groups on the basis of clinical and microbiological criteria. From whole-blood gene expression data, we distinguished patients with sepsis from patients with non-infectious systemic inflammatory conditions using a trained bagged support vector machine (bSVM) classifier (area under the receiver operating characteristic curve (AUC) = 0.81 in the training set; AUC = 0.82 in a held-out validation set). Plasma RNA also yielded a transcriptional signature of sepsis with several genes previously reported as sepsis biomarkers, and a bSVM sepsis diagnostic classifier (AUC = 0.97 training set; AUC = 0.77 validation set). Pathogen detection performance of plasma mNGS varied on the basis of pathogen and site of infection. To improve detection of virus, we developed a secondary transcriptomic classifier (AUC = 0.94 training set; AUC = 0.96 validation set). We combined host and microbial features to develop an integrated sepsis diagnostic model that identified 99% of microbiologically confirmed sepsis cases, and predicted sepsis in 74% of suspected and 89% of indeterminate sepsis cases. In summary, we suggest that integrating host transcriptional profiling and broad-range metagenomic pathogen detection from nucleic acid is a promising tool for sepsis diagnosis., (© 2022. The Author(s).)
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- 2022
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49. Autoantibody discovery across monogenic, acquired, and COVID-19-associated autoimmunity with scalable PhIP-seq.
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Vazquez SE, Mann SA, Bodansky A, Kung AF, Quandt Z, Ferré EMN, Landegren N, Eriksson D, Bastard P, Zhang SY, Liu J, Mitchell A, Proekt I, Yu D, Mandel-Brehm C, Wang CY, Miao B, Sowa G, Zorn K, Chan AY, Tagi VM, Shimizu C, Tremoulet A, Lynch K, Wilson MR, Kämpe O, Dobbs K, Delmonte OM, Bacchetta R, Notarangelo LD, Burns JC, Casanova JL, Lionakis MS, Torgerson TR, Anderson MS, and DeRisi JL
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- Humans, Autoantibodies, Autoantigens metabolism, Autoimmunity, Homeodomain Proteins, Immunoprecipitation, Proteome, Autoimmune Diseases, Bacteriophages metabolism, COVID-19
- Abstract
Phage immunoprecipitation sequencing (PhIP-seq) allows for unbiased, proteome-wide autoantibody discovery across a variety of disease settings, with identification of disease-specific autoantigens providing new insight into previously poorly understood forms of immune dysregulation. Despite several successful implementations of PhIP-seq for autoantigen discovery, including our previous work (Vazquez et al., 2020), current protocols are inherently difficult to scale to accommodate large cohorts of cases and importantly, healthy controls. Here, we develop and validate a high throughput extension of PhIP-seq in various etiologies of autoimmune and inflammatory diseases, including APS1, IPEX, RAG1/2 deficiency, Kawasaki disease (KD), multisystem inflammatory syndrome in children (MIS-C), and finally, mild and severe forms of COVID-19. We demonstrate that these scaled datasets enable machine-learning approaches that result in robust prediction of disease status, as well as the ability to detect both known and novel autoantigens, such as prodynorphin (PDYN) in APS1 patients, and intestinally expressed proteins BEST4 and BTNL8 in IPEX patients. Remarkably, BEST4 antibodies were also found in two patients with RAG1/2 deficiency, one of whom had very early onset IBD. Scaled PhIP-seq examination of both MIS-C and KD demonstrated rare, overlapping antigens, including CGNL1, as well as several strongly enriched putative pneumonia-associated antigens in severe COVID-19, including the endosomal protein EEA1. Together, scaled PhIP-seq provides a valuable tool for broadly assessing both rare and common autoantigen overlap between autoimmune diseases of varying origins and etiologies., Competing Interests: SV, SM, AB, AK, ZQ, EF, NL, DE, PB, SZ, JL, AM, IP, DY, CM, CW, BM, GS, KZ, AC, VT, CS, AT, KL, MW, OK, KD, OD, RB, LN, JB, JC, ML, TT, MA, JD No competing interests declared
- Published
- 2022
- Full Text
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50. Discovery and Genomic Characterization of a Novel Henipavirus, Angavokely Virus, from Fruit Bats in Madagascar.
- Author
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Madera S, Kistler A, Ranaivoson HC, Ahyong V, Andrianiaina A, Andry S, Raharinosy V, Randriambolamanantsoa TH, Ravelomanantsoa NAF, Tato CM, DeRisi JL, Aguilar HC, Lacoste V, Dussart P, Heraud JM, and Brook CE
- Subjects
- Animals, Glycoproteins genetics, Humans, Madagascar, Phylogeny, Urine virology, Zoonoses genetics, Chiroptera genetics, Genome, Viral genetics, Henipavirus classification, Henipavirus genetics, Henipavirus Infections virology, Nipah Virus genetics
- Abstract
The genus Henipavirus (family Paramyxoviridae ) currently comprises seven viruses, four of which have demonstrated prior evidence of zoonotic capacity. These include the biosafety level 4 agents Hendra (HeV) and Nipah (NiV) viruses, which circulate naturally in pteropodid fruit bats. Here, we describe and characterize Angavokely virus (AngV), a divergent henipavirus identified in urine samples from wild, Madagascar fruit bats. We report the nearly complete 16,740-nucleotide genome of AngV, which encodes the six major henipavirus structural proteins (nucleocapsid, phosphoprotein, matrix, fusion, glycoprotein, and L polymerase). Within the phosphoprotein (P) gene, we identify an alternative start codon encoding the AngV C protein and a putative mRNA editing site where the insertion of one or two guanine residues encodes, respectively, additional V and W proteins. In other paramyxovirus systems, C, V, and W are accessory proteins involved in antagonism of host immune responses during infection. Phylogenetic analysis suggests that AngV is ancestral to all four previously described bat henipaviruses-HeV, NiV, Cedar virus (CedV), and Ghanaian bat virus (GhV)-but evolved more recently than rodent- and shrew-derived henipaviruses, Mojiang (MojV), Gamak (GAKV), and Daeryong (DARV) viruses. Predictive structure-based alignments suggest that AngV is unlikely to bind ephrin receptors, which mediate cell entry for all other known bat henipaviruses. Identification of the AngV receptor is needed to clarify the virus's potential host range. The presence of V and W proteins in the AngV genome suggest that the virus could be pathogenic following zoonotic spillover. IMPORTANCE Henipaviruses include highly pathogenic emerging zoonotic viruses, derived from bat, rodent, and shrew reservoirs. Bat-borne Hendra (HeV) and Nipah (NiV) are the most well-known henipaviruses, for which no effective antivirals or vaccines for humans have been described. Here, we report the discovery and characterization of a novel henipavirus, Angavokely virus (AngV), isolated from wild fruit bats in Madagascar. Genomic characterization of AngV reveals all major features associated with pathogenicity in other henipaviruses, suggesting that AngV could be pathogenic following spillover to human hosts. Our work suggests that AngV is an ancestral bat henipavirus that likely uses viral entry pathways distinct from those previously described for HeV and NiV. In Madagascar, bats are consumed as a source of human food, presenting opportunities for cross-species transmission. Characterization of novel henipaviruses and documentation of their pathogenic and zoonotic potential are essential to predicting and preventing the emergence of future zoonoses that cause pandemics.
- Published
- 2022
- Full Text
- View/download PDF
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