Obesity is associated with increased disease severity, elevated viral titers in exhaled breath, and significantly prolonged viral shed during influenza A virus infection. Due to the mutable nature of RNA viruses, we questioned whether obesity could also influence influenza virus population diversity. Here, we show that minor variants rapidly emerge in obese mice. The variants exhibit increased viral replication, resulting in enhanced virulence in wild-type mice. The increased diversity of the viral population correlated with decreased type I interferon responses, and treatment of obese mice with recombinant interferon reduced viral diversity, suggesting that the delayed antiviral response exhibited in obesity permits the emergence of a more virulent influenza virus population. This is not unique to obese mice. Obesity-derived normal human bronchial epithelial (NHBE) cells also showed decreased interferon responses and increased viral replication, suggesting that viral diversity also was impacted in this increasing population.IMPORTANCE Currently, 50% of the adult population worldwide is overweight or obese. In these studies, we demonstrate that obesity not only enhances the severity of influenza infection but also impacts viral diversity. The altered microenvironment associated with obesity supports a more diverse viral quasispecies and affords the emergence of potentially pathogenic variants capable of inducing greater disease severity in lean hosts. This is likely due to the impaired interferon response, which is seen in both obese mice and obesity-derived human bronchial epithelial cells, suggesting that obesity, aside from its impact on influenza virus pathogenesis, permits the stochastic accumulation of potentially pathogenic viral variants, raising concerns about its public health impact as the prevalence of obesity continues to rise.

中文翻译：

---

肥胖相关的微环境促进了强毒流感病毒株的出现。

肥胖与疾病严重程度增加、呼出气中病毒滴度升高以及甲型流感病毒感染期间病毒排出时间显着延长有关。由于 RNA 病毒的易变性，我们质疑肥胖是否也会影响流感病毒种群多样性。在这里，我们展示了在肥胖小鼠中迅速出现的次要变异。这些变体表现出增加的病毒复制，导致野生型小鼠的毒力增强。病毒种群多样性的增加与 I 型干扰素反应的降低相关，用重组干扰素治疗肥胖小鼠会降低病毒多样性，这表明肥胖中表现出的延迟抗病毒反应允许出现更具毒性的流感病毒种群。这并非肥胖小鼠所独有。肥胖衍生的正常人支气管上皮 (NHBE) 细胞也表现出干扰素反应降低和病毒复制增加，这表明病毒多样性在这一不断增长的人口中也受到影响。重要目前，全世界 50% 的成年人超重或肥胖。在这些研究中，我们证明肥胖不仅会增加流感感染的严重程度，还会影响病毒的多样性。与肥胖相关的改变的微环境支持更多样化的病毒准种，并提供能够在瘦宿主中诱导更严重疾病的潜在致病变异的出现。这可能是由于干扰素反应受损，这在肥胖小鼠和肥胖衍生的人支气管上皮细胞中均可见，表明肥胖，