Mice on a high-fat diet have reduced immunopathology and an altered immune response during respiratory syncytial virus infection.

UNLABELLED: Obesity has been identified as an independent risk factor for increased morbidity and mortality during pandemic H1N1 influenza and SARS-CoV-2 infections. Various studies have determined that obese hosts have dysregulated antiviral responses driven by systemic low-grade inflammation, resulting in prolonged viral replication, induction of proinflammatory cytokines during the disease resolution phase, and profound lung parenchymal damage. However, the impact of obesity on disease outcomes in the context of other viral respiratory infections remains unclear. In this study, we sought to understand how obesity affects disease progression during respiratory syncytial virus (RSV) infection using an obese mouse model in which male C57BL/6 mice were fed a high-fat diet (HFD). Mice fed a standard chow diet served as controls. We found that HFD mice exhibited reduced weight loss, illness scores, and histopathological changes after intranasal inoculation with RSV A2. Investigation of potential mechanisms underlying this reduction in severity revealed reduced viral load in obese mice, along with altered innate and adaptive immune responses. Specifically, HFD mice had reduced proinflammatory cytokines in the lungs early in infection and increased CD4+ T cells late in infection. HFD mice also had reduced M2 macrophages in the lungs at 7 days post-infection. Notably, HFD mice infected with RSV did not exhibit aberrant proinflammatory cytokine secretion late in infection, as seen with influenza, likely due to effective viral control. In conclusion, HFD mice exhibited reduced disease severity during RSV infection, associated with decreased viral load and an attenuated but sufficient antiviral response.

IMPORTANCE: Obesity has been shown to induce dysregulated antiviral responses during influenza infections, resulting in extensive morbidity and mortality. No studies to date have investigated how obesity-induced immune dysregulation affects respiratory syncytial virus (RSV) disease progression. RSV has a high global burden, inflicting millions of infections and tens of thousands of deaths yearly, most notably among the very young, the elderly, and those with comorbidities. It is essential to understand how risk factors, such as obesity, affect disease progression to ensure appropriate protection and care for patients. Here, we demonstrate that male C57BL/6 mice fed a high-fat diet had lower viral loads and attenuated inflammatory responses during RSV infection, resulting in reduced morbidity and immunopathology. This pilot study advances our understanding of how obesity affects pulmonary antiviral immunity to RSV and, concurrently, further elucidates RSV pathogenesis.