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.