PMID- 37942334 OWN - NLM STAT- MEDLINE DCOM- 20231110 LR - 20240210 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 14 DP - 2023 TI - Integrated Immunopeptidomic and Proteomic Analysis of COVID-19 lung biopsies. PG - 1269335 LID - 10.3389/fimmu.2023.1269335 [doi] LID - 1269335 AB - INTRODUCTION: Severe respiratory illness is the most prominent manifestation of patients infected with SARS-CoV-2, and yet the molecular mechanisms underlying severe lung disease in COVID-19 affected patients still require elucidation. Human leukocyte antigen class I (HLA-I) expression is crucial for antigen presentation and the host's response to SARS-CoV-2. METHODS: To gain insights into the immune response and molecular pathways involved in severe lung disease, we performed immunopeptidomic and proteomic analyses of lung tissues recovered at four COVID-19 autopsy and six non-COVID-19 transplants. RESULTS: We found signals of tissue injury and regeneration in lung fibroblast and alveolar type I/II cells, resulting in the production of highly immunogenic self-antigens within the lungs of COVID-19 patients. We also identified immune activation of the M2c macrophage as the primary source of HLA-I presentation and immunogenicity in this context. Additionally, we identified 28 lung signatures that can serve as early plasma markers for predicting infection and severe COVID-19 disease. These protein signatures were predominantly expressed in macrophages and epithelial cells and were associated with complement and coagulation cascades. DISCUSSION: Our findings emphasize the significant role of macrophage-mediated immunity in the development of severe lung disease in COVID-19 patients. CI - Copyright (c) 2023 Yin, Klaeger, Chea, Carulli, Rachimi, Black, Filbin, Hariri, Knipe, Padera, Stevens, Lane, Carr, Wu, Kim and Keskin. FAU - Yin, Shanye AU - Yin S AD - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States. AD - Harvard Medical School, Boston, MA, United States. FAU - Klaeger, Susan AU - Klaeger S AD - Broad Institute of MIT and Harvard, Cambridge, MA, United States. FAU - Chea, Vipheaviny A AU - Chea VA AD - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States. AD - Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA, United States. FAU - Carulli, Isabel P AU - Carulli IP AD - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States. AD - Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA, United States. FAU - Rachimi, Suzanna AU - Rachimi S AD - Broad Institute of MIT and Harvard, Cambridge, MA, United States. FAU - Black, Katharine E AU - Black KE AD - Harvard Medical School, Boston, MA, United States. AD - Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, MA, United States. FAU - Filbin, Michael AU - Filbin M AD - Harvard Medical School, Boston, MA, United States. AD - Department of Emergency Medicine, Massachusetts General Hospital, Boston, MA, United States. FAU - Hariri, Lida P AU - Hariri LP AD - Harvard Medical School, Boston, MA, United States. AD - Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, MA, United States. AD - Department of Pathology, Massachusetts General Hospital, Boston, MA, United States. FAU - Knipe, Rachel S AU - Knipe RS AD - Harvard Medical School, Boston, MA, United States. AD - Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, MA, United States. FAU - Padera, Robert F AU - Padera RF AD - Harvard Medical School, Boston, MA, United States. AD - Department of Pathology, Brigham and Women's Hospital, Boston, MA, United States. FAU - Stevens, Jonathan D AU - Stevens JD AD - Department of Pathology, Brigham and Women's Hospital, Boston, MA, United States. FAU - Lane, William J AU - Lane WJ AD - Harvard Medical School, Boston, MA, United States. AD - Department of Pathology, Brigham and Women's Hospital, Boston, MA, United States. FAU - Carr, Steven A AU - Carr SA AD - Broad Institute of MIT and Harvard, Cambridge, MA, United States. FAU - Wu, Catherine J AU - Wu CJ AD - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States. AD - Harvard Medical School, Boston, MA, United States. AD - Broad Institute of MIT and Harvard, Cambridge, MA, United States. AD - Department of Medicine, Brigham and Women's Hospital, Boston, MA, United States. FAU - Kim, Edy Yong AU - Kim EY AD - Harvard Medical School, Boston, MA, United States. AD - Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, United States. FAU - Keskin, Derin B AU - Keskin DB AD - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States. AD - Harvard Medical School, Boston, MA, United States. AD - Broad Institute of MIT and Harvard, Cambridge, MA, United States. AD - Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA, United States. AD - Section for Bioinformatics, Department of Health Technology, Technical University of Denmark, Lyngby, Denmark. AD - Department of Computer Science, Metropolitan College, Boston University, Boston, MA, United States. LA - eng GR - U10 CA180861/CA/NCI NIH HHS/United States GR - K08 HL140175/HL/NHLBI NIH HHS/United States GR - R01 HL152075/HL/NHLBI NIH HHS/United States GR - R03 HL162677/HL/NHLBI NIH HHS/United States GR - R01 HL157174/HL/NHLBI NIH HHS/United States GR - P01 CA206978/CA/NCI NIH HHS/United States GR - K23 HL132120/HL/NHLBI NIH HHS/United States GR - R21 CA267527/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20231020 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 SB - IM MH - Humans MH - *COVID-19/pathology MH - SARS-CoV-2 MH - Proteomics MH - Lung MH - Biopsy PMC - PMC10628763 OTO - NOTNLM OT - COVID-19 - OT - HLA-I OT - immunopeptidome OT - macrophage OT - proteomics COIS- DK is a scientific advisor for Immunitrack and Breakbio. DK owns equity in Affimed N.V., Agenus, Armata Pharmaceuticals, Breakbio, BioMarin Pharmaceutical, Celldex Therapeutics, Editas Medicine, Gilead Sciences, Immunitybio, ImmunoGen, IMV, Lexicon Pharmaceuticals, Neoleukin Therapeutics. BeiGene, a Chinese biotech company, supported unrelated SARS COV-2 research at TIGL. EK has an unrelated financial interest in Novartis AG. EK receives unrelated research funding from Bayer AG and 10x Genomics, Inc. CW receives funding support from Pharmacyclics and holds equity in BioNTech, Inc. SY holds equity in Yihui Bio, Inc. RK receives grant support from Boehringer Ingelheim and Bayer, LH receives grants from Boehringer Ingelheim and has received personal consulting fees from Boehringer Ingelheim, Pliant Therapeutics, Bioclinica, Abbvie and Biogen Idec. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision. EDAT- 2023/11/09 06:42 MHDA- 2023/11/10 06:45 PMCR- 2023/01/01 CRDT- 2023/11/09 04:27 PHST- 2023/07/31 00:00 [received] PHST- 2023/10/09 00:00 [accepted] PHST- 2023/11/10 06:45 [medline] PHST- 2023/11/09 06:42 [pubmed] PHST- 2023/11/09 04:27 [entrez] PHST- 2023/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2023.1269335 [doi] PST - epublish SO - Front Immunol. 2023 Oct 20;14:1269335. doi: 10.3389/fimmu.2023.1269335. eCollection 2023.