Publications

Mark M. Davis, PhD Publications

Mark M. Davis
Director, Stanford Institute for Immunity, Transplantation and Infection and the Burt and Marion Avery Family Professor

Publications

  • Human Coronary Plaque T Cells Are Clonal and Cross-React to Virus and Self. Circulation research Roy Chowdhury, R., D'Addabbo, J., Huang, X., Veizades, S., Sasagawa, K., Louis, D. M., Cheng, P., Sokol, J., Jensen, A., Tso, A., Shankar, V., Wendel, B. S., Bakerman, I., Liang, G., Koyano, T., Fong, R., Nau, A., Ahmad, H., Gopakumar, J. K., Wirka, R., Lee, A., Boyd, J., Woo, Y. J., Quertermous, T., Gulati, G., Jaiswal, S., Chien, Y. H., Chan, C., Davis, M. M., Nguyen, P. K. 2022: 101161CIRCRESAHA121320090

    Abstract

    Once considered primarily a disorder of lipid deposition, coronary artery disease is an incurable, life-threatening disease that is now also characterized by chronic inflammation notable for the buildup of atherosclerotic plaques containing immune cells in various states of activation and differentiation. Understanding how these immune cells contribute to disease progression may lead to the development of novel therapeutic strategies.We used single-cell technology and in vitro assays to interrogate the immune microenvironment of human coronary atherosclerotic plaque at different stages of maturity.In addition to macrophages, we found a high proportion of αβ T cells in the coronary plaques. Most of these T cells lack high expression of CCR7 and L-selectin, indicating that they are primarily antigen-experienced, memory cells. Notably, nearly one-third of these cells express the HLA-DRA surface marker, signifying activation through their TCRs (T-cell receptors). Consistent with this, TCR repertoire analysis confirmed the presence of activated αβ T cells (CD4

    View details for DOI 10.1161/CIRCRESAHA.121.320090

    View details for PubMedID 35430876

  • KIR+CD8+ T cells suppress pathogenic T cells and are active in autoimmune diseases and COVID-19. Science (New York, N.Y.) Li, J., Zaslavsky, M., Su, Y., Guo, J., Sikora, M. J., van Unen, V., Christophersen, A., Chiou, S., Chen, L., Li, J., Ji, X., Wilhelmy, J., McSween, A. M., Palanski, B. A., Mallajosyula, V. V., Bracey, N. A., Dhondalay, G. K., Bhamidipati, K., Pai, J., Kipp, L. B., Dunn, J. E., Hauser, S. L., Oksenberg, J. R., Satpathy, A. T., Robinson, W. H., Dekker, C. L., Steinmetz, L. M., Khosla, C., Utz, P. J., Sollid, L. M., Chien, Y., Heath, J. R., Fernandez-Becker, N. Q., Nadeau, K. C., Saligrama, N., Davis, M. M. 2022: eabi9591

    Abstract

    Here we find that CD8+ T cells expressing inhibitory killer cell immunoglobulin-like receptors (KIRs) are the human equivalent of Ly49+CD8+ regulatory T cells in mice and are increased in the blood and inflamed tissues of patients with a variety of autoimmune diseases. Moreover, these CD8+ T cells efficiently eliminated pathogenic gliadin-specific CD4+ T cells from celiac disease patients' leukocytes in vitro. We also find elevated levels of KIR+CD8+ T cells, but not CD4+ regulatory T cells, in COVID-19 patients, which correlated with disease severity and vasculitis. Selective ablation of Ly49+CD8+ T cells in virus-infected mice led to autoimmunity post infection. Our results indicate that in both species, these regulatory CD8+ T cells act uniquely to suppress pathogenic T cells in autoimmune and infectious diseases.

    View details for DOI 10.1126/science.abi9591

    View details for PubMedID 35258337

  • Minimal Information about MHC Multimers (MIAMM). Journal of immunology (Baltimore, Md. : 1950) Vita, R., Mody, A., Overton, J. A., Buus, S., Haley, S. T., Sette, A., Mallajosyula, V., Davis, M. M., Long, D. L., Willis, R. A., Peters, B., Altman, J. D. 1800; 208 (3): 531-537

    Abstract

    With the goal of improving the reproducibility and annotatability of MHC multimer reagent data, we present the establishment of a new data standard: Minimal Information about MHC Multimers (https://miamm.lji.org/). Multimers are engineered reagents composed of a ligand and a MHC, which can be represented in a standardized format using ontology terminology. We provide an online Web site to host the details of the standard, as well as a validation tool to assist with the adoption of the standard. We hope that this publication will bring increased awareness of Minimal Information about MHC Multimers and drive acceptance, ultimately improving the quality and documentation of multimer data in the scientific literature.

    View details for DOI 10.4049/jimmunol.2100961

    View details for PubMedID 35042788

  • Multiple early factors anticipate post-acute COVID-19 sequelae. Cell Su, Y., Yuan, D., Chen, D. G., Ng, R. H., Wang, K., Choi, J., Li, S., Hong, S., Zhang, R., Xie, J., Kornilov, S. A., Scherler, K., Pavlovitch-Bedzyk, A. J., Dong, S., Lausted, C., Lee, I., Fallen, S., Dai, C. L., Baloni, P., Smith, B., Duvvuri, V. R., Anderson, K. G., Li, J., Yang, F., Duncombe, C. J., McCulloch, D. J., Rostomily, C., Troisch, P., Zhou, J., Mackay, S., DeGottardi, Q., May, D. H., Taniguchi, R., Gittelman, R. M., Klinger, M., Snyder, T. M., Roper, R., Wojciechowska, G., Murray, K., Edmark, R., Evans, S., Jones, L., Zhou, Y., Rowen, L., Liu, R., Chour, W., Algren, H. A., Berrington, W. R., Wallick, J. A., Cochran, R. A., Micikas, M. E., ISB-Swedish COVID-19 Biobanking Unit, Wrin, T., Petropoulos, C. J., Cole, H. R., Fischer, T. D., Wei, W., Hoon, D. S., Price, N. D., Subramanian, N., Hill, J. A., Hadlock, J., Magis, A. T., Ribas, A., Lanier, L. L., Boyd, S. D., Bluestone, J. A., Chu, H., Hood, L., Gottardo, R., Greenberg, P. D., Davis, M. M., Goldman, J. D., Heath, J. R. 2022

    Abstract

    Post-acute sequelae of COVID-19 (PASC) represent an emerging global crisis. However, quantifiable risk factors for PASC and their biological associations are poorly resolved. We executed a deep multi-omic, longitudinal investigation of 309 COVID-19 patients from initial diagnosis to convalescence (2-3months later), integrated with clinical data and patient-reported symptoms. We resolved four PASC-anticipating risk factors at the time of initial COVID-19 diagnosis: type 2 diabetes, SARS-CoV-2 RNAemia, Epstein-Barr virus viremia, and specific auto-antibodies. In patients with gastrointestinal PASC, SARS-CoV-2-specific and CMV-specific CD8+ Tcells exhibited unique dynamics during recovery from COVID-19. Analysis of symptom-associated immunological signatures revealed coordinated immunity polarization into four endotypes, exhibiting divergent acute severity and PASC. We find that immunological associations between PASC factors diminish over time, leading to distinct convalescent immune states. Detectability of most PASC factors at COVID-19 diagnosis emphasizes the importance of early disease measurements for understanding emergent chronic conditions and suggests PASC treatment strategies.

    View details for DOI 10.1016/j.cell.2022.01.014

    View details for PubMedID 35216672

  • Early non-neutralizing, afucosylated antibody responses are associated with COVID-19 severity. Science translational medicine Chakraborty, S., Gonzalez, J. C., Sievers, B. L., Mallajosyula, V., Chakraborty, S., Dubey, M., Ashraf, U., Cheng, B. Y., Kathale, N., Tran, K. Q., Scallan, C., Sinnott, A., Cassidy, A., Chen, S. T., Gelbart, T., Gao, F., Golan, Y., Ji, X., Kim-Schulze, S., Prahl, M., Gaw, S. L., Gnjatic, S., Marron, T. U., Merad, M., Arunachalam, P. S., Boyd, S. D., Davis, M. M., Holubar, M., Khosla, C., Maecker, H. T., Maldonado, Y., Mellins, E. D., Nadeau, K. C., Pulendran, B., Singh, U., Subramanian, A., Utz, P. J., Sherwood, R., Zhang, S., Jagannathan, P., Tan, G. S., Wang, T. T. 1800: eabm7853

    Abstract

    A damaging inflammatory response is implicated in the pathogenesis of severe coronavirus disease 2019 (COVID-19), but mechanisms contributing to this response are unclear. In two prospective cohorts, early non-neutralizing, afucosylated IgG antibodies specific to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were associated with progression from mild to more severe COVID-19. In contrast to the antibody structures that were associated with disease progression, antibodies that were elicited by mRNA SARS-CoV-2 vaccines were instead highly fucosylated and enriched in sialylation, both modifications that reduce the inflammatory potential of IgG. To study the biology afucosylated IgG immune complexes, we developed an in vivo model that revealed that human IgG-Fc gamma receptor (FcgammaR) interactions could regulate inflammation in the lung. Afucosylated IgG immune complexes isolated from COVID-19 patients induced inflammatory cytokine production and robust infiltration of the lung by immune cells. By contrast, vaccine-elicited IgG did not promote an inflammatory lung response. Together, these results show that IgG-FcgammaR interactions are able to regulate inflammation in the lung and may define distinct lung activities associated with the IgG that are associated with severe COVID-19 and protection against infection with SARS-CoV-2.

    View details for DOI 10.1126/scitranslmed.abm7853

    View details for PubMedID 35040666

  • Durability of immune responses to the BNT162b2 mRNA vaccine MED Suthar, M. S., Arunachalam, P. S., Hu, M., Reis, N., Trisal, M., Raeber, O., Chinthrajah, S., Davis-Gardner, M. E., Manning, K., Mudvari, P., Boritz, E., Godbole, S., Henry, A. R., Douek, D. C., Halfmann, P., Kawaoka, Y., Boyd, S. D., Davis, M. M., Zarnitsyna, V. I., Nadeau, K., Pulendran, B. 2022; 3 (1): 25-27

    View details for DOI 10.1016/j.medj.2021.12.005

    View details for Web of Science ID 000758831100004

  • Antibodies elicited by SARS-CoV-2 infection or mRNA vaccines have reduced neutralizing activity against Beta and Omicron pseudoviruses. Science translational medicine Sievers, B. L., Chakraborty, S., Xue, Y., Gelbart, T., Gonzalez, J. C., Cassidy, A. G., Golan, Y., Prahl, M., Gaw, S. L., Arunachalam, P. S., Blish, C. A., Boyd, S. D., Davis, M. M., Jagannathan, P., Nadeau, K. C., Pulendran, B., Singh, U., Scheuermann, R. H., Frieman, M. B., Vashee, S., Wang, T. T., Tan, G. S. 1800: eabn7842

    Abstract

    Multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants that possess mutations associated with increased transmission and antibody escape have arisen over the course of the current pandemic. Although the current vaccines have largely been effective against past variants, the number of mutations found on the Omicron (B.1.1.529) spike protein appear to diminish the protection conferred by pre-existing immunity. Using vesicular stomatitis virus (VSV) pseudoparticles expressing the spike protein of several SARS-CoV-2 variants, we evaluated the magnitude and breadth of the neutralizing antibody response over time in individuals after infection and in mRNA-vaccinated individuals. We observed that boosting increases the magnitude of the antibody response to wildtype (D614), Beta, Delta, and Omicron variants; however, the Omicron variant was the most resistant to neutralization. We further observed that vaccinated healthy adults had robust and broad antibody responses whereas responses may have been reduced in vaccinated pregnant women, underscoring the importance of learning how to maximize mRNA vaccine responses in pregnant populations. Findings from this study show substantial heterogeneity in the magnitude and breadth of responses after infection and mRNA vaccination and may support the addition of more conserved viral antigens to existing SARS-CoV-2 vaccines.

    View details for DOI 10.1126/scitranslmed.abn7842

    View details for PubMedID 35025672

  • Immune imprinting, breadth of variant recognition, and germinal center response in human SARS-CoV-2 infection and vaccination. Cell Röltgen, K., Nielsen, S. C., Silva, O., Younes, S. F., Zaslavsky, M., Costales, C., Yang, F., Wirz, O. F., Solis, D., Hoh, R. A., Wang, A., Arunachalam, P. S., Colburg, D., Zhao, S., Haraguchi, E., Lee, A. S., Shah, M. M., Manohar, M., Chang, I., Gao, F., Mallajosyula, V., Li, C., Liu, J., Shoura, M. J., Sindher, S. B., Parsons, E., Dashdorj, N. J., Dashdorj, N. D., Monroe, R., Serrano, G. E., Beach, T. G., Chinthrajah, R. S., Charville, G. W., Wilbur, J. L., Wohlstadter, J. N., Davis, M. M., Pulendran, B., Troxell, M. L., Sigal, G. B., Natkunam, Y., Pinsky, B. A., Nadeau, K. C., Boyd, S. D. 2022

    Abstract

    During the SARS-CoV-2 pandemic, novel and traditional vaccine strategies have been deployed globally. We investigated whether antibodies stimulated by mRNA vaccination (BNT162b2), including third-dose boosting, differ from those generated by infection or adenoviral (ChAdOx1-S and Gam-COVID-Vac) or inactivated viral (BBIBP-CorV) vaccines. We analyzed human lymph nodes after infection or mRNA vaccination for correlates of serological differences. Antibody breadth against viral variants is lower after infection compared with all vaccines evaluated but improves over several months. Viral variant infection elicits variant-specific antibodies, but prior mRNA vaccination imprints serological responses toward Wuhan-Hu-1 rather than variant antigens. In contrast to disrupted germinal centers (GCs) in lymph nodes during infection, mRNA vaccination stimulates robust GCs containing vaccine mRNA and spike antigen up to 8 weeks postvaccination in some cases. SARS-CoV-2 antibody specificity, breadth, and maturation are affected by imprinting from exposure history and distinct histological and antigenic contexts in infection compared with vaccination.

    View details for DOI 10.1016/j.cell.2022.01.018

    View details for PubMedID 35148837

  • Treatment With Simvastatin and Rifaximin Restores the Plasma Metabolomic Profile in Patients With Decompensated Cirrhosis. Hepatology communications Pose, E., Sola, E., Lozano, J. J., Juanola, A., Sidorova, J., Zaccherini, G., de Wit, K., Uschner, F., Tonon, M., Kazankov, K., Jimenez, C., Campion, D., Napoleone, L., Ma, A. T., Carol, M., Morales-Ruiz, M., Alessandria, C., Beuers, U., Caraceni, P., Francoz, C., Durand, F., Mookerjee, R. P., Trebicka, J., Vargas, V., Piano, S., Watson, H., Abraldes, J. G., Kamath, P. S., Davis, M. M., Gines, P., investigators of the LIVERHOPE Consortium, Schulz, M., Ferstl, P., Giovo, I., Roux, O., Simon-Talero, M., Perez-Guasch, M., Rubio, A. B., Cervera, M., Martinez, S., Fabrellas, N., Pich, J., Vives, A., Avitabile, E., Graupera, I., Sole, C., Bassegoda, O., Gratacos-Gines, J., Joyera, M., Palacio, E., Aban, M., Lanzillotti, T., Nicolao, G., Chiappa, M. T., Esnault, V., Andrade, R., Pavesi, M., Korenjak, M., Farres, J., Serra-Burriel, M., Angeli, P. 1800

    Abstract

    Patients with decompensated cirrhosis, particularly those with acute-on-chronic liver failure (ACLF), show profound alterations in plasma metabolomics. The aim of this study was to investigate the effect of treatment with simvastatin and rifaximin on plasma metabolites of patients with decompensated cirrhosis, specifically on compounds characteristic of the ACLF plasma metabolomic profile. Two cohorts of patients were investigated. The first was a descriptive cohort of patients with decompensated cirrhosis (n=42), with and without ACLF. The second was an intervention cohort from the LIVERHOPE-SAFETY randomized, double-blind, placebo-controlled trial treated with simvastatin 20mg/day plus rifaximin 1,200mg/day (n=12) or matching placebo (n=13) for 3months. Plasma samples were analyzed using ultrahigh performance liquid chromatography-tandem mass spectroscopy for plasma metabolomics characterization. ACLF was characterized by intense proteolysis and lipid alterations, specifically in pathways associated with inflammation and mitochondrial dysfunction, such as the tryptophan-kynurenine and carnitine beta-oxidation pathways. An ACLF-specific signature was identified. Treatment with simvastatin and rifaximin was associated with changes in 161 of 985 metabolites in comparison to treatment with placebo. A remarkable reduction in levels of metabolites from the tryptophan-kynurenine and carnitine pathways was found. Notably, 18 of the 32 metabolites of the ACLF signature were affected by the treatment. Conclusion: Treatment with simvastatin and rifaximin modulates some of the pathways that appear to be key in ACLF development. This study unveils some of the mechanisms involved in the effects of treatment with simvastatin and rifaximin in decompensated cirrhosis and sets the stage for the use of metabolomics to investigate new targeted therapies in cirrhosis to prevent ACLF development.

    View details for DOI 10.1002/hep4.1881

    View details for PubMedID 34964311

  • Alloantigen-specific type 1 regulatory T cells suppress through CTLA-4 and PD-1 pathways and persist long-term in patients. Science translational medicine Chen, P. P., Cepika, A., Agarwal-Hashmi, R., Saini, G., Uyeda, M. J., Louis, D. M., Cieniewicz, B., Narula, M., Amaya Hernandez, L. C., Harre, N., Xu, L., Thomas, B. C., Ji, X., Shiraz, P., Tate, K. M., Margittai, D., Bhatia, N., Meyer, E., Bertaina, A., Davis, M. M., Bacchetta, R., Roncarolo, M. G. 2021; 13 (617): eabf5264

    Abstract

    [Figure: see text].

    View details for DOI 10.1126/scitranslmed.abf5264

    View details for PubMedID 34705520

  • Single-cell sequencing unveils distinct immune microenvironments with CCR6-CCL20 crosstalk in human chronic pancreatitis. Gut Lee, B., Namkoong, H., Yang, Y., Huang, H., Heller, D., Szot, G. L., Davis, M. M., Husain, S. Z., Pandol, S. J., Bellin, M. D., Habtezion, A. 2021

    Abstract

    OBJECTIVE: Chronic pancreatitis (CP) is a potentially fatal disease of the exocrine pancreas, with no specific or effective approved therapies. Due to difficulty in accessing pancreas tissues, little is known about local immune responses or pathogenesis in human CP. We sought to characterise pancreatic immune responses using tissues derived from patients with different aetiologies of CP and non-CP organ donors in order to identify key signalling molecules associated with human CP.DESIGN: We performed single-cell level cellular indexing of transcriptomes and epitopes by sequencing and T-cell receptor (TCR) sequencing of pancreatic immune cells isolated from organ donors, hereditary and idiopathic patients with CP who underwent total pancreatectomy. We validated gene expression data by performing flow cytometry and functional assays in a second patient with CP cohort.RESULTS: Deep single-cell sequencing revealed distinct immune characteristics and significantly enriched CCR6+ CD4+ T cells in hereditary compared with idiopathic CP. In hereditary CP, a reduction in T-cell clonality was observed due to the increased CD4+ T (Th) cells that replaced tissue-resident CD8+ T cells. Shared TCR clonotype analysis among T-cell lineages also unveiled unique interactions between CCR6+ Th and Th1 subsets, and TCR clustering analysis showed unique common antigen binding motifs in hereditary CP. In addition, we observed a significant upregulation of the CCR6 ligand (CCL20) expression among monocytes in hereditary CP as compared with those in idiopathic CP. The functional significance of CCR6 expression in CD4+ T cells was confirmed by flow cytometry and chemotaxis assay.CONCLUSION: Single-cell sequencing with pancreatic immune cells in human CP highlights pancreas-specific immune crosstalk through the CCR6-CCL20 axis, a signalling pathway that might be leveraged as a potential future target in human hereditary CP.

    View details for DOI 10.1136/gutjnl-2021-324546

    View details for PubMedID 34702715

  • CD4+ T cells contribute to neurodegeneration in Lewy body dementia. Science (New York, N.Y.) Gate, D., Tapp, E., Leventhal, O., Shahid, M., Nonninger, T. J., Yang, A. C., Strempfl, K., Unger, M. S., Fehlmann, T., Oh, H., Channappa, D., Henderson, V. W., Keller, A., Aigner, L., Galasko, D. R., Davis, M. M., Poston, K. L., Wyss-Coray, T. 2021: eabf7266

    Abstract

    [Figure: see text].

    View details for DOI 10.1126/science.abf7266

    View details for PubMedID 34648304

  • Functional Consequences of Memory Inflation after Solid Organ Transplantation. Journal of immunology (Baltimore, Md. : 1950) Higdon, L. E., Schaffert, S., Cohen, R. H., Montez-Rath, M. E., Lucia, M., Saligrama, N., Margulies, K. B., Martinez, O. M., Tan, J. C., Davis, M. M., Khatri, P., Maltzman, J. S. 2021

    Abstract

    CMV is a major infectious complication following solid organ transplantation. Reactivation of CMV leads to memory inflation, a process in which CD8 T cells expand over time. Memory inflation is associated with specific changes in T cell function, including increased oligoclonality, decreased cytokine production, and terminal differentiation. To address whether memory inflation during the first year after transplantation in human subjects alters T cell differentiation and function, we employed single-cell-matched TCRalphabeta and targeted gene expression sequencing. Expanded T cell clones exhibited a terminally differentiated, immunosenescent, and polyfunctional phenotype whereas rare clones were less differentiated. Clonal expansion occurring between pre- and 3 mo posttransplant was accompanied by enhancement of polyfunctionality. In contrast, polyfunctionality and differentiation state were largely maintained between 3 and 12 mo posttransplant. Highly expanded clones had a higher degree of polyfunctionality than rare clones. Thus, CMV-responsive CD8 T cells differentiated during the pre- to posttransplant period then maintained their differentiation state and functional capacity despite posttransplant clonal expansion.

    View details for DOI 10.4049/jimmunol.2100405

    View details for PubMedID 34551963

  • Evolution of Cytomegalovirus-Responsive T Cell Clonality following Solid Organ Transplantation. Journal of immunology (Baltimore, Md. : 1950) Higdon, L. E., Schaffert, S., Huang, H., Montez-Rath, M. E., Lucia, M., Jha, A., Saligrama, N., Margulies, K. B., Martinez, O. M., Davis, M. M., Khatri, P., Maltzman, J. S. 2021

    Abstract

    CMV infection is a significant complication after solid organ transplantation. We used single cell TCR alphabeta sequencing to determine how memory inflation impacts clonality and diversity of the CMV-responsive CD8 and CD4 T cell repertoire in the first year after transplantation in human subjects. We observed CD8 T cell inflation but no changes in clonal diversity, indicating homeostatic stability in clones. In contrast, the CD4 repertoire was diverse and stable over time, with no evidence of CMV-responsive CD4 T cell expansion. We identified shared CDR3 TCR motifs among patients but no public CMV-specific TCRs. Temporal changes in clonality in response to transplantation and in the absence of detectable viral reactivation suggest changes in the repertoire immediately after transplantation followed by an expansion with stable clonal competition that may mediate protection.

    View details for DOI 10.4049/jimmunol.2100404

    View details for PubMedID 34551964

  • Effective Viral Vector SARS-CoV-2 Booster Vaccination in a Patient with Rheumatoid Arthritis after Initial Ineffective mRNA Vaccine Response. Arthritis & rheumatology (Hoboken, N.J.) Baker, M. C., Mallajosyula, V., Davis, M. M., Boyd, S. D., Nadeau, K. C., Robinson, W. H. 2021

    Abstract

    Managing patients with rheumatic disease during the COVID-19 pandemic has posed a unique challenge. Immunosuppressed patients are at an increased risk for developing severe COVID-19 and may not derive full protection from the vaccine (1-5). Thus, it is paramount we develop strategies whereby rheumatic disease patients can be protected from the pandemic virus and its variants.

    View details for DOI 10.1002/art.41978

    View details for PubMedID 34514750

  • Immunophenotyping assessment in a COVID-19 cohort (IMPACC): A prospective longitudinal study SCIENCE IMMUNOLOGY Rouphael, N., Maecker, H., Montgomery, R. R., Diray-Arce, J., Kleinstein, S. H., Altman, M. C., Bosinger, S. E., Eckalbar, W., Guan, L., Hough, C. L., Krammer, F., Langelier, C., Levy, O., McEnaney, K., Peters, B., Rahman, A., Rajan, J., Sigelman, S., Steen, H., van Bakel, H., Ward, A., Wilson, M. R., Woodruff, P., Zamecnik, C. R., Augustine, A. D., Al Ozonoff, Reed, E. F., Becker, P. M., Higuita, N., Altman, M. C., Atkinson, M. A., Baden, L. R., Bime, C., Brakenridge, S. C., Calfee, C. S., Cairns, C. B., Corry, D., Davis, M. M., Ehrlich, L. R., Haddad, E. K., Erle, D. J., Fernandez-Sesma, A., Hafler, D. A., Kheradmand, F., Kraft, M., McComsey, G. A., Melamed, E., Messer, W., Metcalf, J., Nadeau, K. C., Pulendran, B., Rouphaell, N., Sarwal, M., Schaenman, J., Sekaly, R., Shaw, A. C., Simon, V., IMPACC Manuscript Writing Team, IMPACC Network Steering Comm 2021; 6 (62)

    Abstract

    The IMmunoPhenotyping Assessment in a COVID-19 Cohort (IMPACC) is a prospective longitudinal study designed to enroll 1000 hospitalized patients with COVID-19 (NCT04378777). IMPACC collects detailed clinical, laboratory and radiographic data along with longitudinal biologic sampling of blood and respiratory secretions for in depth testing. Clinical and lab data are integrated to identify immunologic, virologic, proteomic, metabolomic and genomic features of COVID-19-related susceptibility, severity and disease progression. The goals of IMPACC are to better understand the contributions of pathogen dynamics and host immune responses to the severity and course of COVID-19 and to generate hypotheses for identification of biomarkers and effective therapeutics, including optimal timing of such interventions. In this report we summarize the IMPACC study design and protocols including clinical criteria and recruitment, multi-site standardized sample collection and processing, virologic and immunologic assays, harmonization of assay protocols, high-level analyses and the data sharing plans.

    View details for DOI 10.1126/sciimmunol.abf3733

    View details for Web of Science ID 000684294900003

    View details for PubMedID 34376480

  • Single-cell Sequencing Unveils Distinct Immune Microenvironment in Human Chronic Pancreatitis Lee, B., Namkoong, H., Yang, Y., Huang, H., Heller, D., Szot, G., Davis, M., Pandol, S. J., Bellin, M. D., Husain, S., Habtezion, A. LIPPINCOTT WILLIAMS & WILKINS. 2021: 1073

    View details for Web of Science ID 000706786400147

  • Association of Longitudinal Changes in Skeletal Muscle Mass With Survival in Patients With Pancreatic Cancer Lee, B., Namkoong, H., Yang, Y., Huang, H., Heller, D., Szot, G., Davis, M., Pandol, S. J., Bellin, M. D., Husain, S., Habtezion, A. LIPPINCOTT WILLIAMS & WILKINS. 2021: 1073

    View details for Web of Science ID 000706786400146

  • CD8+ T cells specific for conserved coronavirus epitopes correlate with milder disease in COVID-19 patients. Science immunology Mallajosyula, V., Ganjavi, C., Chakraborty, S., McSween, A. M., Pavlovitch-Bedzyk, A. J., Wilhelmy, J., Nau, A., Manohar, M., Nadeau, K. C., Davis, M. M. 2021; 6 (61)

    Abstract

    A central feature of the SARS-CoV-2 pandemic is that some individuals become severely ill or die, whereas others have only a mild disease course or are asymptomatic. Here we report development of an improved multimeric alphabeta T cell staining reagent platform, with each maxi-ferritin "spheromer" displaying 12 peptide-MHC complexes. Spheromers stain specific T cells more efficiently than peptide-MHC tetramers and capture a broader portion of the sequence repertoire for a given peptide-MHC. Analyzing the response in unexposed individuals, we find that T cells recognizing peptides conserved amongst coronaviruses are more abundant and tend to have a "memory" phenotype, compared to those unique to SARS-CoV-2. Significantly, CD8+ T cells with these conserved specificities are much more abundant in COVID-19 patients with mild disease versus those with a more severe illness, suggesting a protective role.

    View details for DOI 10.1126/sciimmunol.abg5669

    View details for PubMedID 34210785

  • An inflammatory aging clock (iAge) based on deep learning tracks multimorbidity, immunosenescence, frailty and cardiovascular aging. Nature aging Sayed, N., Huang, Y., Nguyen, K., Krejciova-Rajaniemi, Z., Grawe, A. P., Gao, T., Tibshirani, R., Hastie, T., Alpert, A., Cui, L., Kuznetsova, T., Rosenberg-Hasson, Y., Ostan, R., Monti, D., Lehallier, B., Shen-Orr, S. S., Maecker, H. T., Dekker, C. L., Wyss-Coray, T., Franceschi, C., Jojic, V., Haddad, F., Montoya, J. G., Wu, J. C., Davis, M. M., Furman, D. 2021; 1: 598-615

    Abstract

    While many diseases of aging have been linked to the immunological system, immune metrics capable of identifying the most at-risk individuals are lacking. From the blood immunome of 1,001 individuals aged 8-96 years, we developed a deep-learning method based on patterns of systemic age-related inflammation. The resulting inflammatory clock of aging (iAge) tracked with multimorbidity, immunosenescence, frailty and cardiovascular aging, and is also associated with exceptional longevity in centenarians. The strongest contributor to iAge was the chemokine CXCL9, which was involved in cardiac aging, adverse cardiac remodeling and poor vascular function. Furthermore, aging endothelial cells in human and mice show loss of function, cellular senescence and hallmark phenotypes of arterial stiffness, all of which are reversed by silencing CXCL9. In conclusion, we identify a key role of CXCL9 in age-related chronic inflammation and derive a metric for multimorbidity that can be utilized for the early detection of age-related clinical phenotypes.

    View details for DOI 10.1038/s43587-021-00082-y

    View details for PubMedID 34888528