During the 2009 pandemic H1N1 (pH1N1) influenza outbreak, obese individuals were at greater risk for morbidity and mortality to pandemic infection. However, the mechanisms contributing to greater infection severity in obese individuals remain unclear. Although most individuals lacked pre-existing, neutralizing antibody protection to the novel pH1N1 virus, heterologous defenses conferred from exposure to circulating strains or vaccination have been shown to impart protection against pH1N1 infection in humans and mice. Because obese humans and mice have impaired memory T-cell and antibody responses following influenza vaccination or infection, we investigated the impact of obesity on heterologous protection to pH1N1 infection using a mouse model of diet-induced obesity. Lean and obese mice were infected with influenza A/PR/8/34 and five weeks later challenged with a lethal dose of heterologous pH1N1 (A/Cal/04/09). Cross-neutralizing antibody protection was absent in this model, but obese mice exhibited a significantly lower level of non-neutralizing, cross-reactive pH1N1 nucleoprotein antibodies following the primary PR/8 infection. Further, obese mice had elevated viral titers, greater lung inflammation, lung damage, and an increased number of cytotoxic memory CD8+ T cells in the lung airways. Although obese mice had more regulatory T cells (Tregs) in the lung airways compared with lean controls during the pH1N1 challenge, Tregs isolated from obese mice were 40% less suppressive than Tregs isolated from lean mice. Taken together, excessive inflammatory responses to pH1N1 infection, potentially due to greater viral burden and impaired Treg function, may be a novel mechanism by which obesity contributes to greater pH1N1 severity
