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Infection, autoimmunity, and cancer are principal human health challenges of the 21 st century. Often regarded as distinct ends of the immunological spectrum, recent studies hint at potential overlap between these diseases. For example, inflammation can be pathogenic in infection and autoimmunity. T resident memory (T RM ) cells can be beneficial in infection and cancer. However, these findings are limited by size and scope; exact immunological factors shared across diseases remain elusive. Here, we integrate large-scale deeply clinically and biologically phenotyped human cohorts of 526 patients with infection, 162 with lupus, and 11,180 with cancer. We identify an NKG2A + immune bias as associative with protection against disease severity, mortality, and autoimmune/post-acute chronic disease. We reveal that NKG2A + CD8 + T cells correlate with reduced inflammation and increased humoral immunity and that they resemble T RM cells. Our results suggest NKG2A + biases as a cross-disease factor of protection, supporting suggestions of immunological overlap between infection, autoimmunity, and cancer., Competing Interests: Declaration of interests J.R.H. is a consultant for Regeneron Pharmaceuticals. J.D.G. reports contracted research, a grant, and consulting fees from Gilead. K.M.C. reports being a shareholder in Geneoscopy LLC and has received consulting fees from Geneoscopy LLC, PACT Pharma, Tango Therapeutics, Flagship Labs 81 LLC, and the Rare Cancer Research Foundation., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

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 (2-3 months 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 + T cells 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., Competing Interests: Declaration of interests J.R.H. and A.R. are founders and board members of PACT Pharma. J.R.H. is a board member of Isoplexis, and A.R. is the scientific advisor to Isoplexis. M.M.D. is a member of the Scientific Advisory Board of PACT Pharma. J.A.B. is a member of the Scientific Advisory Boards of Arcus, Solid, and VIR. J.A.B. is a member of the Board of Directors of Gilead and Provention. J.A.B. is the CEO of Sonoma Biotherapeutics. L.L.L. is on the scientific advisory boards of Alector, Atreca, Dragonfly, DrenBio, Nkarta, Obsidian Therapeutics, and SBI Biotech. R.G. has received consulting income from Juno Therapeutics, Takeda, Infotech Soft, Celgene, and Merck, has received research support from Janssen Pharmaceuticals and Juno Therapeutics, and declares ownership in CellSpace Biosciences. P.D.G. is on the Scientific Advisory Board of Celsius, Earli, Elpiscience, Immunoscape, Rapt, and Nextech, was a scientific founder of Juno Therapeutics, and receives research support from Lonza. J.D.G. declared contracted research with Gilead, Lilly, and Regeneron. J.A.H. received consulting fees or honoraria from Gilead Sciences, Amplyx, Allovir, Allogene therapeutics, CRISPR therapeutics, CSL Behring, OptumHealth, Octapharma, and Takeda and research funding from Takeda, Allovir, Karius, and Gilead Sciences. Q.D., D.H.M., R.T., R.M.G., M.K., and T.M.S. have employment and equity ownership with Adaptive Biotechnologies. The remaining authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

We present an integrated analysis of the clinical measurements, immune cells, and plasma multi-omics of 139 COVID-19 patients representing all levels of disease severity, from serial blood draws collected during the first week of infection following diagnosis. We identify a major shift between mild and moderate disease, at which point elevated inflammatory signaling is accompanied by the loss of specific classes of metabolites and metabolic processes. Within this stressed plasma environment at moderate disease, multiple unusual immune cell phenotypes emerge and amplify with increasing disease severity. We condensed over 120,000 immune features into a single axis to capture how different immune cell classes coordinate in response to SARS-CoV-2. This immune-response axis independently aligns with the major plasma composition changes, with clinical metrics of blood clotting, and with the sharp transition between mild and moderate disease. This study suggests that moderate disease may provide the most effective setting for therapeutic intervention., Competing Interests: Declaration of Interests J.R.H. is founder and board member of Isoplexis and PACT Pharma. M.M.D. is a member of the Scientific Advisory Board of PACT Pharma. J.A.B. is a member of the Scientific Advisory Boards of Arcus, Celsius, and VIR. J.A.B. is a member of the Board of Directors of Rheos and Provention. J.A.B. has recently joined Sonoma Biotherapeutics as President and CEO. Sonoma Biotherapeutics is involved in developing novel Treg-based cell therapies for the treatment of autoimmune diseases. R.G. has received consulting income from Juno Therapeutics, Takeda, Infotech Soft, Celgene, Merck and has received research support from Janssen Pharmaceuticals and Juno Therapeutics, and declares ownership in CellSpace Biosciences. P.D.G is on the Scientific Advisory Board of Celsius, Earli, Elpiscience, Immunoscape, Rapt, and Nextech, was a scientific founder of Juno Therapeutics, and receives research support from Lonza. J.D.G. declared contracted research with Gilead, Lilly, and Regeneron. The remaining authors declare no competing interests., (Published by Elsevier Inc.)