INVESTIGATION OF RECOVERY FOLLOWING SARS-COV-2 INFECTION: CLINICAL DISEASE, PATHOGENESIS, AND IMMUNE DURABILITY
Date
2024-03-27
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
ORCID
0000-0002-7212-7487
Type
Thesis
Degree Level
Masters
Abstract
SARS-CoV-2 continues to present unique challenges to global health as a proportion of
people recovering from COVID-19 deal with prolonged symptoms and the threat of re-infection
with antigenically divergent variants. Throughout my three project objectives, I address the
unknowns of SARS-CoV-2 recovery utilizing both preclinical and clinical studies of COVID-19
recovery addressing post-acute sequelae of COVID-19 (PASC) and immune durability. In
Objective 1, Syrian hamsters were infected with SARS-CoV-2 and sampled over one-year to
assess viral load, pathology, antibody levels, and gene expression profiles by RNA sequencing.
Long-term analysis of infected hamsters indicated persistent SARS-CoV-2 RNA and protein
months after acute infection, prolonged lung damage, sustained complement activation pathways
and neutrophils present in the lungs, along with dysregulation of serotonin secretion genes in the
brain of previously infected hamsters. In Objective 2, I investigated the clinical characteristics
and systemic immune profiles of individuals recovering from COVID-19 using a cross-sectional
study in humans. Participants were recruited across five groups including those with and without
PASC from the Saskatoon area to provide information on their COVID-19 experience and
provide a blood sample. Antibody responses were assessed by ELISA and viral neutralization
assays, and cytokine profiles were determined by Ella SimplePlex Immunoassay. Individuals
with PASC had decreased levels of neutralizing antibodies toward SARS-CoV-2 and Omicron
BA.1. Sex analysis indicated that female PASC participants had sustained inflammatory
cytokines such as GM-CSF following COVID-19 while males had decreasing concentrations
over time. Lastly, in Objective 3, I utilized homologous variant re-inoculations in C57Bl6/J mice
using the Alpha variant of SARS-CoV-2 to understand the durability of long-term immunity at
challenge. Mice were protected from re-infection at both day 21 and 56 post-primary infection.
However, by day 84 mice were susceptible to re-infection indicating decayed protective immune
responses. Overall, key attributes of recovery after SARS-CoV-2 infection were identified
including viral antigen persistence, prolonged lung damage, dysregulated immune responses, sex
differences, and decaying protection from re-infection. Taken together, these findings may be
applied to PASC diagnostic development, treatment evaluation, as well as public health policies
and vaccine regimens for vulnerable groups with higher susceptibility to PASC.
Description
Keywords
SARS-CoV-2, Post-acute sequelae of COVID-19
Citation
Degree
Master of Science (M.Sc.)
Department
Microbiology and Immunology
Program
Microbiology and Immunology