HOST RESPONSE TO PRIMARY AND SECONDARY CORONAVIRUS EXPOSURES AND POTENTIAL GERMINAL CENTER MECHANISMS ASSOCIATED WITH PROTECTION DURING RE-EXPOSURE
Date
2024-09-27
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
ORCID
0000-0002-8339-2454
Type
Thesis
Degree Level
Doctoral
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in late 2019, causing coronavirus disease 2019 (COVID-19), a disease of varying symptoms and degrees of severity. As the virus spread globally, it was clear that certain demographics of people were more likely to experience severe disease. Additionally, seasonally circulating coronaviruses predate SARS-CoV-2. Therefore, it was hypothesized that factors such as host sex, age, and pre-existing immunity could influence SARS-CoV-2 infection outcomes. To address this hypothesis, I developed three objectives, leveraging the development of preclinical animal models in order to assess viral pathogenicity and host immune response regulation in the context of host factors. In my first objective, I created preclinical models for coronavirus infection suitable for pathological and immunological analyses. First, I developed a SARS-CoV-2 ferret model and investigated the influence of sex and age on SARS-CoV-2 infection outcomes. Aged male ferrets exhibited decreased antiviral capabilities resulting in prolonged infection. Second, I developed a Syrian hamster model, revealing widespread inflammation and organ damage beyond respiratory organs. In objective two I investigated the impact of previous coronavirus infections on immune recall during subsequent coronavirus exposures in a Syrian hamster model. While prior infection with seasonal coronaviruses offered limited protection against SARS-CoV-2, distinct germinal center response signatures were observed depending on the antigenic similarity between primary and secondary inoculations. To gain more insight into the germinal center response, my third objective examined memory establishment and recall following SARS-CoV-2 variant secondary exposures in a wildtype mouse model. Protection against a secondary exposure correlated with increased germinal center B cells in the mediastinal lymph node for homologous secondary exposures. Heterologous secondary exposures appeared to be more dependent on a T follicular helper cell response and were not protected against re-exposure. Increased viral loads occurred during later secondary exposures when both germinal center B cells and T follicular helper cell levels had contracted, suggesting the importance of maintaining these cell types for long-term protection. In conclusion, this work advances our understanding of host factors age, sex, and pre-existing immunity on SARS-CoV-2 pathology and offers a potential mechanism of protection against re-exposure.
Description
Keywords
Coronavirus, SARS-CoV-2, COVID-19, Immune memory, Germinal center response, Host factors, Pre-existing immunity, Age, Sex
Citation
Degree
Doctor of Philosophy (Ph.D.)
Department
Biochemistry, Microbiology and Immunology
Program
Microbiology and Immunology