Integrated Immunopeptidomic and Proteomic Analysis of COVID-19 lung biopsies.

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.

Innate T cells in the intensive care unit.

Rapid onset of acute inflammation is a hallmark of critical illnesses that bring patients to the intensive care unit (ICU). In critical illness, innate T cells rapidly reach full activation and drive a robust acute inflammatory response. As "cellular adjuvants," innate T cells worsen inflammation and mortality in several common critical illnesses including sepsis, ischemia-reperfusion injury, stroke, and exacerbations of respiratory disease. Interestingly, innate T cell subsets can also promote a protective and anti-inflammatory response in sepsis, ischemia-reperfusion injury, and asthma. Therapies that target innate T cells have been validated in several models of critical illness. Here, we review the role of natural killer T (NKT) cells, mucosal-associated invariant T (MAIT) cells and γδ T cells in clinical and experimental critical illness.