Malnutrition, including both undernutrition and obesity, affects millions of people globally and is persistently on the rise. Obesity affects ~13% of adults globally and was identified as a risk factor for worse disease outcomes after the H1N1 influenza pandemic of 2009 and has since been shown to aggravate disease outcomes of respiratory viruses like severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and mosquito-borne viruses like West Nile Virus (WNV), chikungunya virus (CHIKV) and Mayaro virus (MAYV) and reduce the vaccine efficacy for influenza and SARS-CoV-2. Obesity is associated with a chronic state of inflammation and dysregulated immune response which has been proposed to be one of the mechanisms driving the severity of coronavirus disease 2019 (COVID-19). These altered signatures or biomarkers might be associated with disease outcome and prognosis. Therefore, animal models reflecting the clinical outcomes and natural immune responses observed in humans are crucial to identifying reliable biomarkers. Using mouse hepatitis virus 1 (MHV-1) as a model for SARS-CoV-2, we established obesity as a risk factor and identified biomarkers and pathways associated with worse disease outcomes.
Obesity rates in low and middle-income countries (LMICs) are approaching levels found in high-income countries (HICs). Mosquito-borne viral diseases like dengue, chikungunya, and Zika pose a significant threat to LMICs and cause huge health and economic losses. Obesity was shown to worsen alphavirus pathogenesis, but interestingly, it also reduced their transmission by mosquitoes. Given the global prevalence of obesity and mosquito-borne viruses, it is critical to understand how obesity drives reduced alphavirus transmission. Using a natural transmission cycle between lean and obese mice and mosquitoes, we confirmed that obesity reduced the transmission potential of alphaviruses like CHIKV and MAYV and activated the Toll pathway in mosquito midguts. Various genes and other pathways were also altered in response to obese bloodmeal at various time-points post-bloodmeal; however, one gene, AAEL009965, was downregulated in the mosquito midguts 1-day-post-bloodmeal and its knockdown led to reduced infection rates and titers in mosquitoes. Through this thesis, we aimed to utilize obesity as a tool to identify biomarkers to predict coronavirus disease outcomes and design effective alphavirus transmission control strategies. / Doctor of Philosophy / Obesity, a global epidemic associated with chronic systemic inflammation, has emerged as an independent risk factor following infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The impact of obesity on COVID-19 severity, largely based on epidemiological data or research with non-natural hosts of SARS-CoV-2, necessitates the use of natural models of obesity to study the host's response to coronaviruses. Here we used mouse models of diet-induced obesity and infected them with a mouse coronavirus to account for the host's natural immune response against the virus. We showed that obesity exacerbates disease outcomes and identified various genes associated with disease severity in obese mice that correspond to the gene expression patterns in severe COVID-19 patients. These findings underscore the critical role of obesity in disease outcomes and pave the way for further research in this area.
Obesity also worsens the disease outcome following infection with mosquito-borne alphaviruses like chikungunya (CHIKV) and Mayaro (MAYV), however, its impact on the vector's transmission potential is poorly understood. Using a natural transmission cycle between lean and obese mice and mosquitoes, we showed that obesity reduced alphavirus transmission by mosquitoes. We found altered expression of specific genes and pathways, in mosquito midguts exposed to alphavirus-infected obese bloodmeal compared to the lean ones and their knockdown led to altered infection rates in mosquitoes suggestive of their role in viral infection of mosquitoes. We also established insulin as a potential antiviral factor in obese bloodmeal. Therefore, these studies provide the basic framework for understanding the impact of obesity on viral transmission and pathogenesis by using relevant animal models. Furthermore, these studies utilize obesity as a tool to identify predictors of severe disease outcomes and identify genes that could be used as potential transmission control strategies for various mosquito-borne viruses.
| Identifer | oai:union.ndltd.org:VTETD/oai:vtechworks.lib.vt.edu:10919/119145 |
| Date | 28 May 2024 |
| Creators | Rai, Pallavi |
| Contributors | Biomedical and Veterinary Sciences, Weger, James David, Paulson, Sally L., LeRoith, Tanya, Duggal, Nisha K. |
| Publisher | Virginia Tech |
| Source Sets | Virginia Tech Theses and Dissertation |
| Language | English |
| Detected Language | English |
| Type | Dissertation |
| Format | ETD, application/pdf |
| Rights | In Copyright, http://rightsstatements.org/vocab/InC/1.0/ |
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