Date of Award

2023

Document Type

Thesis

Degree Name

Master of Science (MS)

Department

Microbiology and Molecular Genetics

First Advisor

Nimrat Chatterjee

Abstract

Dengue virus (DENV) is the fastest-spreading arthropod-borne virus in the world. Dengue is characterized as a major global public health challenge in tropical and subtropical nations by the World Health Organization. The number of dengue cases globally has increased 8-fold in the past two decades, with 100 to 400 million cases occurring annually. While most patients with dengue fever are asymptomatic, dengue infection carries the possibility of severe and potentially fatal febrile illness. Approximately 1 in 4 individuals infected with dengue virus develop symptomatic dengue infection, often presenting as mild to moderate, nonspecific, acute febrile illness. A smaller subset of these individuals, about 1 in 20 infected with DENV, go on to develop severe dengue. Dengue fever is characterized by a high fever, headache, rash, myalgia, arthralgia, and stomachache. Dengue fever can progress into severe dengue, characterized by thrombocytopenia, vascular leakage, hypotension, and potentially fatal hypovolemic shock.

Given the COVID-19 pandemic, RNA virus research has been spotlighted across several fields, including DNA repair and genome instability. Recently, we have shown that SARS-CoV-2, an enveloped, positive sense RNA virus of the Coronaviridae family, triggers a DNA damage response in host cells and upregulates genome instability markers in human lung cells, Golden Syrian Hamster lung tissues, COVID-19 autopsy lung tissues, and blood sera from patients with acute COVID-19 and post-COVID. Specifically, we observed host cell genetic alterations, such as increased HPRT-mutagenesis, telomere length dysregulation, and elevated microsatellite instability (MSI).

In addition to this, emerging evidence has suggested that DENV-dependent modulation of host cell genome instability should be investigated. It is known that viruses of the Flaviviridae family, including DENV, trigger oxidative stress, which has been implicated in the pathogenesis of many diseases and cancers. Considering this, a recent preliminary study discovered a positive correlation between DNA damage, apoptosis, and oxidative stress during DENV infection. Epidemiologically, in 2020, a population-based cohort study through the National Health Insurance Research Databases in Taiwan provided the first epidemiologic evidence for the association between dengue virus infection and leukemia, suggesting a possible association between DENV infection and cancer incidence.

Here, we report host genome instability post-DENV infection in Vero E6 cells, as observed by global repression of DNA repair pathways. Specifically, we report suppression of essential homologous recombination, mismatch repair, Fanconi anemia, non-homologous end joining, base excision repair, nucleotide excision repair, DNA damage response, and cellular stress response genes. In addition, we see an increase in the mutagenic translesion synthesis polymerase, POL. Strikingly, we discovered pre-treatment with JH-RE-06.NaOH, a small molecule inhibitor of the mutagenic translesion synthesis pathway, nearly completely suppresses DENV infection in Vero E6 cells. This result suggests a novel link between dengue virus and the translesion synthesis pathway and highlights the therapeutic potential of JH-RE-06 for patients with acute dengue infection.

Language

en

Number of Pages

108 p.

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