Contribution of adipose tissue immune cells to Influenza pathogenesis - SUMMARY Epidemiological evidence establishes obesity as an independent risk factor for increased severity of viral respiratory pneumonias including influenza virus infection. Dysregulated systemic and tissue inflammation is critical to the pathogenesis of both influenza- and obesity-comorbidities. However, the critical processes that govern increased influenza severity in obesity remain undefined. The expansion of white adipose tissue (WAT) along with activation of WAT-residing immune cells inflammation promotes tissue/organ damage severity in obesity. Of note, WAT depots differ in their anatomical location and function—characteristics that are directly linked with the pathogenesis of disease-impacted organs. Using a model that combines obesity and influenza A virus (IAV) infection we reported that obese mice exhibit in greater mortality and worsened lung inflammation and tissue pathology compared to lean controls. Focusing on immune cells, we showed that IAV infection changes epididymal WAT (eWAT; a depot distal to the lungs) and lung immune cell composition and function, and favors accrual of a macrophage (MØ) subset in the lungs that shares a transcriptomic signature with eWAT residing inflammatory MØs. However, although transfer of eWAT MØ from obese into lean IAV infected mice amplified host immune cell infiltration to the lungs, it was not sufficient to increase influenza severity. Thus, eWAT MØ, although important, either do not possess the full extent of pathogenic traits or other WAT-residing immune cells are dominant contributors to influenza severity in obesity. Importantly, the presence of thoracic WAT (tWAT; a depot that is proximal to the lungs) was reported in individuals living with obesity and in obese mice. Notably, adipocytes and MØ within tWAT support IAV replication and produce proinflammatory factors during IAV infection. However, whether the character and function of tWAT and eWAT immune cells, including MØ, differs during IAV infection has not been studied. Our preliminary studies comparing tWAT and eWAT immune cells show that: (i) transfer of tWAT immune cells from obese mice into IAV infected lean mice induces mortality; (ii) tWAT is highly enriched in phenotypically distinct immune cell types; and (iii) tWAT MØ exhibit greater ability to produce proinflammatory cytokines relevant in influenza pathogenesis. Together, our novel data and existing literature support the overarching hypothesis that tWAT MØ become progressively more proinflammatory during obesity and IAV infection, and that activation of tWAT MØ unique pathogenic traits is sufficient to increases influenza severity. To test this hypothesis, we will: (1) Determine cellular traits of tWAT immune cells in obesity and influenza severity; and (2) Determine pathological processes whereby tWAT macrophages exacerbate influenza severity. Given the global increase in the incidence of obesity and viral pneumonias (e.g., Influenza, SARS-CoV-2) our high-risk/high-reward proposal will provide keen insights into previously unexplored processes that govern inflammation-associated disease severity in obesity.
