RAJATAVA Basu
$655,369
UNIV OF NORTH CAROLINA CHAPEL HILL
North Carolina
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Obesity is associated with chronic inflammation and an impaired immune response to infection from select viruses, including influenza and SARS-CoV-2, leading to increased morbidity and mortality. Many studies have demonstrated a critical role for CD4+ and CD8+ T cells in this setting, with primary and memory T cell responses to viral infection impaired in mice and humans with obesity. Given the high prevalence of obesity and viral infections with influenza and coronavirus worldwide, it is critically important to understand T cell dysfunction in obesity and identify novel strategies to improve T cell responses to infection in this high-risk population. T cell function and metabolism are closely linked, and many studies have demonstrated that changes to CD4+ and CD8+ T cell metabolism influence T cell fate and function. We have found that activated CD4+ T cells from obese mice have an altered metabolic profile characterized by increased glucose uptake and increased mitochondrial oxidation. This represents a unique cellular metabolic phenotype that may mechanistically explain obesity- associated T cell dysfunction. Interestingly, weight loss was unable to normalize adipose inflammation, reverse altered T cell metabolism, or improve the impaired immune response to influenza in obese mice. In contrast; systemic treatment of obese mice with metformin reversed CD4+ T cell metabolic dysfunction and improved survival following influenza infection. The clinical relevance and importance of this finding are supported by multiple observational and retrospective studies over the last few years showing that patients taking metformin have reduced disease severity and mortality to both influenza and COVID. Multiple lines of evidence point to a key role for metformin in regulating T cell immune responses. First, metformin has been found to alter the gut microbiome, which we know to influence both tissue-specific and systemic inflammation, and thereby influence T cells indirectly. Second, metformin has been shown to attenuate several inflammatory diseases by regulating the balance of regulatory and effector T cells. Third, we have generated preliminary data in our lab showing that metformin decreases oxidative metabolism, as well as the production of inflammatory cytokines in activated CD4+ and CD8+ T cells and differentiated Th1 and Th17 cells in vitro, indicating a direct effect of metformin on T cells. Therefore, the overall objective of this proposal is to elucidate the mechanisms by which metformin regulates T cell metabolism and function, directly and indirectly, using mouse models and human samples. To do so, we will perform the following aims: (1) Identify changes in gut microbiome and inflammatory cytokines in obese mice treated with metformin and determine if these changes drive T cell responses; (2) Determine the molecular mechanisms by which metformin directly affects T cell metabolism and function; and (3) Test if treatment with metformin can reverse obesity-associated dysfunction in human T cells. Successful completion of these aims will identify mechanisms by which metformin regulates T cell metabolism and function and reveal novel targets to improve treatment to viral infection in patients with obesity.