The Role of Obesity on Alphavirus Disease Severity

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Project Summary/Abstract Chikungunya virus (CHIKV), an NIAID category B pathogen, causes a debilitating arthritic disease that can last for years. A massive outbreak of CHIKV occurred throughout the Americas in 2013, with an estimated 39.9 million people infected. Closely related viruses include Ross River virus (RRV) and Mayaro virus (MAYV), which produce thousands of annual cases of arthritic disease in Australia and South America, respectively. While previous research demonstrates that the host immune response mediates the disease caused by these viruses, little is known about the host cofactors that act as risk factors for severe disease caused by these viruses. One host cofactor—obesity, which affects 42.4% of Americans and 1 in 8 people worldwide—has been associated with disease severity during infection with several viruses; including, Influenza virus, SARS-CoV-2, and dengue virus. Similarly, our recent experimental data suggest that obese mice infected with either CHIKV, RRV, or MAYV experience more severe disease outcomes. Furthermore, we have identified several cytokines and chemokines that correlate strongly with obesity in our mouse model during infection. Our long-term goals are: (i) to identify novel therapeutic targets to treat severe alphavirus disease and (ii) to increase our fundamental knowledge regarding the underlying mechanisms associated with the increased disease severity in obese people caused by several viral pathogens towards reducing illness and disability. The objectives of this proposal, directed towards attaining our long-term goal, are to (i) define the role of obesity- associated immune genes on alphavirus pathogenesis in lean and obese hosts and (ii) define the interplay between macrophages, NK cells, and neutrophils with obesity in the context of alphavirus infection. Our central hypothesis is that pro-inflammatory cytokines induced by obesity promote an increase in disease severity upon alphavirus infection by altering infiltration and activation of several immune cell populations. These studies' rationale is two-fold: (i) to define obesity's impact on alphavirus disease severity and (ii) to use obesity to identify host gene candidates to develop novel therapeutics. In Aim 1, we will use knockout mice, depletion, and cytokine treatment to determine the impact of several cytokines that strongly correlate with bodyweight in infected mice, which we expect will lead to a better understanding of alphavirus pathogenesis and identify therapeutic targets. In Aim 2, we will use flow cytometry and transcriptomics to define the impact of obesity on immune cell infiltration and activation during alphavirus infection, which we expect will provide novel insight into immune mediators of pathogenesis in lean and obese hosts, which can be targeted by therapeutics. The proposed studies seek to provide insight into the fundamental relationship between obesity and alphavirus pathogenesis and identify novel therapeutic targets towards reducing alphavirus disease.