Molecular Mechanisms Behind Sars-Cov-2 Induced Host Genome Restructuring

<p>Severe Acute Respiratory Syndrome Coronavirus -2 (SARS-CoV-2) has caused unprecedented morbidity and mortality worldwide.<strong> </strong>There are two pathophysiological hallmarks associated with severe patient outcomes after SARS-CoV-2 acute infection, namely delayed/weakened interferon production and overactive inflammatory responses. Our previous work has shown that these altered immune responses are due, at least in part, to significant alterations in 3D genome organization and epigenetic landscape following SARS-CoV-2 infection that are distinct from and more severe than changes caused by other viral infections or immune stimulants. While these changes at the chromatin level are important for understanding the immune dysregulation seen in some cases of COVID-19, the underlying viral mechanism by which these changes occur remains unclear. We hypothesize that viral proteins encoded by the SARS-CoV-2 RNA genome directly impact host chromatin to confer the observed immune-related transcriptional perturbations. Using systems of inducible expression for select SARS-CoV-2 proteins, we have examined their activities in terms of cellular localization, chromatin interaction, and impact on anti-viral gene expression. Thus far, our preliminary evidence suggests that two specific SARS-CoV-2 proteins can enter the host nucleus and that, when expressed individually, can exert transcriptional regulatory impacts of varying detriment to the host immune-related gene expression. These viral proteins have also been found to associate with chromatin during biochemical fractionation of SARS-CoV-2 infected cells. Finally, specific genomic loci and the associated chromatin features with which our target viral proteins interact have been identified, giving us a clue into how viral proteins might work to achieve transcriptional perturbation during infection. Characterization of individual SARS-CoV-2 proteins and their impact on host chromatin provides important insight into how this virus restructures the host genome to alter immune response gene expression and how this contributes to COVID-19 patient pathology.</p>

Name thesis:degree_name

Masters of Science (MS)

Level thesis:degree_level

Thesis (MS)

Year dc:date.available

2023

Authors dc:creator

• Simpson, Erin
• <p>0000-0002-1658-5846</p>

Contributors dc:contributor

• Wenbo Li
• Jichao Chen
• Danielle Garsin

• SARS-CoV-2
• chromatin
• transcription regulation
• immune response
• epigenetics
• viral infection
• Immunity
• Immunology of Infectious Disease
• Laboratory and Basic Science Research
• Molecular Genetics
• Virology

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1297

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2354