Virobe · Immunometabolic regulation of the host response to viral infection in the context of obesity

Chronic viral diseases are of significant concern to the public health due to lack of effective vaccines and paucity of potent anti-viral medication. Notably, individuals with obesity exhibit higher morbidity and mortality due to viral diseases. However, what specific mechanisms underlie the confounding effects of obesity on the overt outcome of viral infections remains poorly understood. In pre-clinical studies, I found that obese mice developed profound and progressive loss of fat and muscle in response to chronic viral infection, while metabolically healthy animals showed only transient and significantly milder manifestation of tissue wasting in response to the virus. In this proposal, I aim to identify the mechanisms driving this marked and progressive tissue wasting in infected obese mice. Inflammation and disrupted glucose homeostasis have been implicated to play a role in tissue wasting. I hypothesize that the profound tissue wasting during viral infection results from uncontrolled glucose homeostasis, perturbations in macrophage functions and from abnormal cytokine profiles observed in the context of obesity. I will test my hypothesis using high-fat diet-induced mouse model of obesity infected with chronic strain of the lymphocytic choriomeningitis virus. I will test the involvement of cytokines, macrophages as well as of glucose homeostasis in the progressive wasting in infected obese animals and evaluate if there is a crosstalk between these three factors during infection in an obese host. This project will generate critical knowledge to address why host response to virus is disrupted in the context of obesity and identify potential therapeutic strategies for improving the outcome of viral diseases such as tissue wasting in this metabolic disease. Moreover, this study will highlight the crosstalk between the immune system and body metabolism during infection and will help to better understand the processes underlying immunity to pathogens.