Clinical proteomics of pneumonia — antibody-mediated immunopathology in COVID-19

Semenova, Anna (2024): Clinical proteomics of pneumonia — antibody-mediated immunopathology in COVID-19. Dissertation, LMU München: Medizinische Fakultät

Abstract

Infectious respiratory diseases comprise the 4th most fatal group of diseases worldwide. COVID-19 patients exhibit unique pathophysiology, which is not observed in pneumonia caused by other respiratory viruses or bacterial pathogens with similar severity. Most COVID-19 studies lack appropriate comparisons to other viral types of pneumonia, hindering the development of biomarkers for early identification of high-risk COVID-19 patients. This study aims to investigate the humoral immune responses and identify distinct proteomics signatures associated with COVID-19 compared to influenza and bacterial pneumonia. Moreover, the project specifically focuses on unraveling autoimmune aspects of severe COVID-19. I applied proteomic profiling to bronchoalveolar lavage fluid (BALF) and plasma samples from pneumonia patients of the SCRIPT cohort at Northwestern Memorial Hospital (NMH) Chicago and assessed the enrichment of molecular signatures unique to COVID-19 (n=13), influenza (n=7), and bacterial pneumonia (n=6) patients at up to five time points after intubation in the intensive care unit. Emphasizing persistent proteomic signatures during hospitalization, I outlined plasma- and lung-abundant proteins and revealed upregulation of immunoglobulin production in the bronchoalveolar environment specific to SARS-CoV-2 infection. Secondly, utilizing a single-cell multi-omic dataset of COVID-19 patients (n=102) at mild and severe stages, I identified the overrepresentation of immunoglobulin V-domains connected to COVID-19 severity. Furthermore, my findings elucidated the transcriptomic and surface protein markers of plasma cell populations, contributing to COVID-19-specific humoral immune responses observed in the BALF of Chicago cohort. Lastly, I applied a Differential Antibody Capture (DAC) assay on two independent cohorts of acute COVID-19 patients to capture plasma antibodies that show affinity to native lung proteins. I identified 93 putative autoantibody targets specific to COVID-19 patients, with 19 targets in common in both cohorts. Among the putative autoantigens, I observed extracellular matrix, complement regulation, nuclear antigens, and immune regulatory proteins. Besides that, the dynamic changes in autoantibody patterns were correlated with clinical parameters, revealing the effect of individual autoantibodies and overall autoreactivity on severe COVID-19 immunopathology. This was demonstrated by the significant correlation of the cumulative autoantigen coefficient with a length of intubation, aspartate transaminase (AST), alanine transaminase (ALT), Troponin I, and procalcitonin, indicating prolonged recovery periods, multi-organ damage, and increased susceptibility to secondary bacterial infections. My work improves the understanding of unique proteomic features specific to COVID-19 pneumonia, revealing the upregulation of complement cascade, platelet degranulation proteins, and immunoglobulins in the lung environment. Besides that, the research sheds light on the development of autoantibody responses during the acute phase of infection, thus providing potential biomarkers to improve the diagnosis in uncertain cases and identify severe COVID-19 trajectories at an early stage.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften ; 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Fakultäten: Medizinische Fakultät
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 9. Dezember 2024
• 1. Bericht­erstatter:in: Behr, Jürgen