The late 2019 marked the onset of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that led to the unprecedented COVID-19 pandemic, with profound global health and socioeconomic impacts. This thesis offers a thorough examination of the molecular biology, evolution, and disease-causing mechanisms of SARS-CoV-2, as well as recent advancements in understanding the structural and functional implications of mutations in viral proteins.
The prevailing belief is that SARS-CoV-2 originated from a zoonotic transmission involving bats as the natural reservoir hosts, with an unknown intermediate host facilitating transmission to humans. Genomic sequencing and phylogenetic analysis have identified similarities between SARS-CoV-2 and bat coronaviruses, particularly RaTG13, indicating a potential bat origin. However, the exact circumstances and intermediate hosts of the spillover event remain under investigation.
In its structure, SARS-CoV-2 is an enveloped virus with a positive-sense single-stranded RNA genome. This genome encodes both structural and non-structural proteins crucial for viral replication and the development of the disease. The spike (S) protein facilitates viral entry by binding to the angiotensin-converting enzyme 2 (ACE2) receptor. Meanwhile, non-structural proteins are involved in viral RNA synthesis, immune evasion, and the assembly of virions. Alterations in the genetic makeup of the SARS-CoV-2 genome, notably within the spike protein, can impact transmission efficiency, viral load, and immune evasion. Notable mutations such as D614G, N501Y, and E484K have been associated with increased transmissibility and reduced neutralization by antibodies. Understanding the effects of these mutations on viral fitness and pathogenicity is crucial for informing public health interventions and vaccine development efforts. The impacts of Non-structural proteins (NSPs) on viral replication and transmission are however understudied.
In this study, we focused on mutations in the several NSPs including NSP1, 2, 3, 13,14, and 15 of the early Omicron (BA.1) and XBB 1.5 variants and investigated their impact on structure and the functional implications using bioinformatics tools and protein structure prediction methods. Our analysis focused on potential alterations in NSP1's structure and hence its ability to suppress host gene expression and modulate immune responses, shedding light on the mechanisms by which SARS-CoV-2 evolves to evade host defenses.
Overall, this thesis gives insights into the emergence, structure, replication cycle, evolution, and pathogenesis of SARS-CoV-2, highlighting the importance of ongoing research efforts in understanding and combatting this global health threat and provides a detailed structural analysis of mutations in NSPs. / Master of Science / The COVID-19 pandemic, instigated by the virus referred to as SARS-CoV-2, is a novel coronavirus believed to have originated in bats and possibly transmitted to humans via an intermediate host. Its genetic structure and protein interactions play crucial roles in how it spreads and causes illness. We need to understand where the virus came from, how it's built, it's life cycle and how it's changing over time.
While the virus has undergone a lot of mutations over time, scientists are actively studying these changes, with a lot of focus on the structural ones, to understand their implications for public health measures and vaccine development. In our study, we focus on the non- structural proteins and aim to investigate the effect of selected mutations on the protein structure and function using bioinformatics. Understanding the virus is essential for effectively combating future pandemics and safeguarding public health.
| Identifer | oai:union.ndltd.org:VTETD/oai:vtechworks.lib.vt.edu:10919/119452 |
| Date | 14 June 2024 |
| Creators | Datsomor, Eugenia Afi |
| Contributors | Biological Sciences, Capelluto, Daniel G., Finkielstein, Carla V., Schubot, Florian David, Huckle, William R. |
| Publisher | Virginia Tech |
| Source Sets | Virginia Tech Theses and Dissertation |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | ETD, application/pdf |
| Rights | In Copyright, http://rightsstatements.org/vocab/InC/1.0/ |
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