Date of Award
Spring 2024
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Immunobiology
First Advisor
Iwasaki, Akiko
Abstract
Since its introduction into humans in late 2019, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread globally and resulted in the deaths of more than 6.5 million people in just 39 months. Infection with SARS-CoV-2 causes Coronavirus Disease 2019 (COVID-19), a clinically heterogenous viral illness that may alternatively manifest as asymptomatic infection or a life-threatening viral pneumonia. This dissertation examines the range of pathogenic and protective immune responses generated in humans with COVID-19, with specific focus on the contribution of various maladaptive immune responses to the development of severe disease. The investigations presented here are organized into 4 chapters, each published sequentially during the COVID-19 pandemic. Broadly, Chapters 1-3 focus on acute SARS-CoV-2 infection and explore the role of maladaptive (1-2) and protective (3) immune responses in regulating severity of COVID-19 among a cohort of hospitalized patients. Chapter 4 examines the biological basis of persistent sequalae among a separate cohort of individuals experiencing incomplete recovery more than a year following their acute SARS-CoV-2 infection. In Chapter 1, I profile the disorganized immune response provoked by SARS-CoV-2 infection among a cohort of hospitalized COVID-19 patients. Longitudinal examination of peripheral immune responses revealed four distinct clusters of immune response programs among COVID-19 patients that correlated with clinical outcomes. Immune response programs most associated with poor clinical outcomes demonstrated profound inflammatory responses involving simultaneous engagement of Type I, Type II, and Type III immune responses, with elevated IFN-α and IL-1 family cytokines (IL-18, IL-1a, IL-1b) additionally identified as significant predictors of fatal disease through statistical modeling. In Chapter 2, the production of diverse, functional autoantibodies during COVID-19 is described. Autoantibodies targeting a broad range of tissues and cell surface proteins were identified in acute COVID-19 patients, with severe patients having the highest frequency of autoantibodies detected. Subsequent in vitro assays and in vivo model systems established the functional nature of these self-targeting antibodies, and in the case of immune-effector targeting autoantibodies, correlations with impaired immune responses targeting SARS-CoV-2 infection were established. In Chapter 3, I examine the dynamics of protective, neutralizing antibody responses against SARS-CoV-2. Initial investigations into the relative importance of the total magnitude of anti-SARS-CoV-2 antibody responses in mediating protection from fatal disease were unrevealing. Instead, longitudinal analyses demonstrated stark differences in the kinetics of humoral responses, particularly among neutralizing antibody species, between fatal and non-fatal cases of COVID-19. These results critically highlighted that delays in neutralizing antibody production efficiently predict poor clinical outcomes among patients hospitalized with COVID-19. In Chapter 4, the biological basis of post-acute sequelae of COVID-19 (PASC) or ‘Long COVID’ is investigated in a demographically matched cohort of individuals. Through high-dimensional immunophenotyping of individuals with Long COVID, I identified significant biological differences in individuals with Long COVID relative to various convalescent and control populations. Subsequent integration of immune phenotyping data into machine learning models identified a minimal set of soluble protein factors that accurately distinguish Long COVID from healthy and convalescent controls.
Recommended Citation
Klein, Jonathan, "Pathological and Protective Immune Responses During COVID-19" (2024). Yale Graduate School of Arts and Sciences Dissertations. 1256.
https://elischolar.library.yale.edu/gsas_dissertations/1256
