Department of Nutrition, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
J Immunol. 2013 Sep 1;191(5):2474-85. doi: 10.4049/jimmunol.1202429. Epub 2013 Jul 31.
During the 2009 pandemic H1N1 influenza A virus (pH1N1) outbreak, obese individuals were at greater risk for morbidity and mortality from pandemic infection. However, the mechanisms contributing to greater infection severity in obese individuals remain unclear. Although most individuals lacked pre-existing, neutralizing Ab 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 Ab responses following influenza vaccination or infection, we investigated the impact of obesity on heterologous protection from pH1N1 infection using a mouse model of diet-induced obesity. Lean and obese mice were infected with influenza A/Puerto Rico/8/34 (PR8) and 5 wk later challenged with a lethal dose of heterologous pH1N1. Cross-neutralizing Ab protection was absent in this model, but obese mice exhibited a significantly lower level of nonneutralizing, cross-reactive pH1N1 nucleoprotein Abs following the primary PR8 infection. Further, obese mice had elevated viral titers, greater lung inflammation and lung damage, and more cytotoxic memory CD8(+) T cells in the lung airways. Although obese mice had more regulatory T cells (Tregs) in the lung airways than did lean controls during the pH1N1 challenge, Tregs isolated from obese mice were 40% less suppressive than Tregs isolated from lean mice. In sum, excessive inflammatory responses to pH1N1 infection, potentially owing to greater viral burden and impaired Treg function, may be a novel mechanism by which obesity contributes to greater pH1N1 severity.
在 2009 年大流行的甲型 H1N1 流感病毒（pH1N1）爆发期间，肥胖个体在大流行感染的发病率和死亡率方面风险更高。然而，导致肥胖个体感染严重程度增加的机制尚不清楚。尽管大多数个体缺乏针对新型 pH1N1 病毒的预先存在的中和抗体保护，但从循环株暴露或接种疫苗中获得的异源防御已被证明可以在人类和小鼠中提供对 pH1N1 感染的保护。由于肥胖的人类和小鼠在流感疫苗接种或感染后会出现记忆 T 细胞和 Ab 反应受损，因此我们使用饮食诱导肥胖的小鼠模型研究了肥胖对 pH1N1 感染的异源保护的影响。瘦鼠和肥胖鼠感染甲型流感 A/Puerto Rico/8/34（PR8），5 周后用致死剂量的异源 pH1N1 进行挑战。在该模型中不存在交叉中和抗体保护，但肥胖鼠在原发性 PR8 感染后表现出明显较低水平的非中和、交叉反应性 pH1N1 核蛋白抗体。此外，肥胖鼠的病毒滴度更高，肺部炎症和肺损伤更大，肺气道中的细胞毒性记忆 CD8（+）T 细胞更多。尽管肥胖鼠在 pH1N1 挑战期间肺气道中的调节性 T 细胞（Tregs）比瘦对照鼠多，但从肥胖鼠中分离的 Tregs 的抑制作用比从瘦鼠中分离的 Tregs 低 40%。总之，对 pH1N1 感染的过度炎症反应，可能由于病毒负担增加和 Treg 功能受损，可能是肥胖导致 pH1N1 严重程度增加的新机制。
