Impact of obesity on antiviral NK cell function and immune crosstalk with respiratory epithelial cells during influenza virus infection

RESEARCH SUMMARY Respiratory infections, including those caused by influenza A virus (IAV), significantly contribute to worldwide mortality and morbidity. Vulnerable populations, such as individuals with obesity, have been found to have increased susceptibility to respiratory infections. The prevalence of obesity, defined as a Body Mass Index (BMI) greater than 30, has been steadily increasing over the past decades. Obesity is known to be associated with elevated inflammation and dysregulated immunity, but the specific mechanisms through which innate immunity contributes to the increased risk of infection remain unknown. Natural killer (NK) cells are critical to the innate immune response against viral infections, including IAV. NK cells play a crucial role in early viral clearance by detecting and eliminating viral-infected respiratory epithelial cells (RECs) and producing antiviral IFN-γ cytokines. Previous studies have shown that obesity can interfere with NK cell function in the context of cancer and other diseases. However, the impact of obesity on NK cell antiviral responses, particularly during IAV infection, remains to be investigated. Based on the existing knowledge gaps, I hypothesize that NK cells from obese individuals exhibit blunted function during IAV infection, leading to a disruption in NK cell-epithelial cell crosstalk. This disruption may contribute to increased susceptibility and severity of infection in obese individuals. The primary objective of this research is to identify the specific contribution of NK cells to the increased susceptibility and disease severity observed in obesity. Specific Aim 1 will assess the impact of obesity on NK cell populations and function in response to IAV infection in both systemic and mucosal compartments. This will be achieved by comprehensively analyzing NK cell phenotypic and functional characteristics using advanced flow cytometry and transcriptomic profiling of nasal wash samples. Specific Aim 2 will investigate the crosstalk between NK cells and RECs during IAV infection in the context of obesity. The goal is to determine if NK cell dysfunction and epithelial cell susceptibility to infection contribute to increased viral replication and decreased NK cell cytotoxicity. Additionally, the potential therapeutic effect of metformin, a drug commonly used for diabetes and weight loss, on reversing the impairment of NK-epithelial cell crosstalk in obesity will be evaluated. By employing a multidisciplinary approach involving advanced techniques such as RNA transcriptomics, complex flow cytometry, and primary cell coculture systems, I will enhance my understanding of NK cell antiviral responses in the context of obesity. The findings from these studies will contribute to our understanding of how obesity affects innate immune responses in high-risk populations and their susceptibility to respiratory infections. The collaborative environment and resources at St. Jude provide an ideal setting for conducting this research and facilitating the researcher's career development in mucosal immunity.