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Characterization of IFN Signaling Dysregulation and Functional Role of SARS-CoV-2 Protease PLpro in COVID-19 Pathogenesis

Rezene, Sefanit (2023) MOBN03 20222
Degree Projects in Molecular Biology
Popular Abstract
SARS-CoV-2 Antagonism of IFN Signalling Pathways.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). The rapid spread of the virus raised concerns for the major gap in knowledge of infectious viral diseases. Understanding how the virus modulates host innate immune responses is crucial for development of therapeutic strategies.

COVID-19 has spread globally with <750 million confirmed cases and <6 million deaths (as of June 2023) associated with the disease. The broad spectrum of the disease makes it difficult to develop widely applicable therapeutic strategies. Understanding the driving factors of disease severity and target specific viral components may aid in... (More)
SARS-CoV-2 Antagonism of IFN Signalling Pathways.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). The rapid spread of the virus raised concerns for the major gap in knowledge of infectious viral diseases. Understanding how the virus modulates host innate immune responses is crucial for development of therapeutic strategies.

COVID-19 has spread globally with <750 million confirmed cases and <6 million deaths (as of June 2023) associated with the disease. The broad spectrum of the disease makes it difficult to develop widely applicable therapeutic strategies. Understanding the driving factors of disease severity and target specific viral components may aid in combating infectious pathogens more efficiently.

Our work intended to narrow the gap in knowledge by 1. Investigating the role of IFN-signaling components in disease severity, and 2. Clarifying the functional significance of the SARS-CoV-2 encoded papain-like protease (PLpro) in dysregulating the innate immune response via interfering with post-translational modifications.

Here, we report that plasma IFN levels in patient cohorts were poor indicators of disease state. Interestingly, we observed translational blocks in patients with severe COVID-19, indicating a possible mechanism by which the virus is driving disease severity. Next, we characterized PLpro. PLpro has secondary functions as a deubiquitinase (DUB) and deISGylase (deISG) and can dysregulate important regulatory functions of the host innate immune response. We observed distinct DUB and deISG activity by PLpro wildtype, catalytic mutant, ubiquitin and ISG15 binding mutants. We also observed that PLpro interacts with host-substrates that have functions in mounting antiviral responses against SARS-CoV-2. This work provides novel targets for potential therapeutic strategies that may aid in limiting the virulence of SARS-CoV-2. Additionally, we report possible driving factors that may help our understanding of how and why certain patients develop severe disease.

Master’s Degree Project in Molecular Biology 60 credits 2023
Department of Biology, Lund University

Advisor: David O’Carroll
Department of Biology (Less)
Please use this url to cite or link to this publication:
author
Rezene, Sefanit
supervisor
organization
course
MOBN03 20222
year
type
H2 - Master's Degree (Two Years)
subject
language
English
id
9135698
date added to LUP
2023-08-30 15:33:15
date last changed
2023-08-30 15:33:15
@misc{9135698,
  author       = {{Rezene, Sefanit}},
  language     = {{eng}},
  note         = {{Student Paper}},
  title        = {{Characterization of IFN Signaling Dysregulation and Functional Role of SARS-CoV-2 Protease PLpro in COVID-19 Pathogenesis}},
  year         = {{2023}},
}