Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
mBio. 2017 Sep 19;8(5):e00889-17. doi: 10.1128/mBio.00889-17.
Obesity is a risk factor for developing severe disease following influenza virus infection; however, the comorbidity of obesity and secondary bacterial infection, a serious complication of influenza virus infections, is unknown. To fill this gap in knowledge, lean and obese C57BL/6 mice were infected with a nonlethal dose of influenza virus followed by a nonlethal dose of Strikingly, not only did significantly enhanced death occur in obese coinfected mice compared to lean controls, but also high mortality was seen irrespective of influenza virus strain, bacterial strain, or timing of coinfection. This result was unexpected, given that most influenza virus strains, especially seasonal human A and B viruses, are nonlethal in this model. Both viral and bacterial titers were increased in the upper respiratory tract and lungs of obese animals as early as days 1 and 2 post-bacterial infection, leading to a significant decrease in lung function. This increased bacterial load correlated with extensive cellular damage and upregulation of platelet-activating factor receptor, a host receptor central to pneumococcal invasion. Importantly, while vaccination of obese mice against either influenza virus or pneumococcus failed to confer protection, antibiotic treatment was able to resolve secondary bacterial infection-associated mortality. Overall, secondary bacterial pneumonia could be a widespread, unaddressed public health problem in an increasingly obese population. Worldwide obesity rates have continued to increase. Obesity is associated with increased severity of influenza virus infection; however, very little is known about respiratory coinfections in this expanding, high-risk population. Our studies utilized a coinfection model to show that obesity increases mortality from secondary bacterial infection following influenza virus challenge through a "perfect storm" of host factors that lead to excessive viral and bacterial outgrowth. In addition, we found that vaccination of obese mice against either virus or bacteria failed to confer protection against coinfection, but antibiotic treatment did alleviate mortality. Combined, these results represent an understudied and imminent public health concern in a weighty portion of the global population.
肥胖是感染流感病毒后发生严重疾病的一个风险因素；然而，肥胖与继发性细菌感染的合并症（流感病毒感染的严重并发症）尚不清楚。为了填补这一知识空白，瘦鼠和肥胖鼠 C57BL/6 被感染了非致死剂量的流感病毒，随后又被感染了非致死剂量的肺炎链球菌。令人惊讶的是，与瘦对照相比，肥胖合并感染的老鼠不仅死亡率显著增加，而且无论流感病毒株、细菌株或合并感染的时间如何，死亡率都很高。鉴于大多数流感病毒株，尤其是季节性的人 A 型和 B 型病毒，在这种模型中是非致命的，因此这个结果出人意料。肥胖动物的上呼吸道和肺部的病毒和细菌滴度早在细菌感染后第 1 天和第 2 天就升高，导致肺功能显著下降。这种细菌负荷的增加与广泛的细胞损伤和血小板激活因子受体的上调有关，血小板激活因子受体是肺炎球菌入侵的宿主受体的核心。重要的是，虽然肥胖小鼠接种流感病毒或肺炎球菌疫苗不能提供保护，但抗生素治疗可以解决继发性细菌感染相关的死亡率。总的来说，继发性细菌性肺炎可能是肥胖人群中一个广泛存在但未得到解决的公共卫生问题。全世界的肥胖率一直在持续上升。肥胖与流感病毒感染的严重程度增加有关；然而，对于这个不断扩大的高危人群中的呼吸道合并感染，人们知之甚少。我们的研究利用一种合并感染模型表明，肥胖通过导致病毒和细菌过度生长的宿主因素“完美风暴”，增加了流感病毒感染后继发性细菌感染的死亡率。此外，我们发现肥胖小鼠接种流感病毒或细菌疫苗不能提供针对合并感染的保护，但抗生素治疗确实减轻了死亡率。综合这些结果，代表了在全球相当一部分人口中一个研究不足且迫在眉睫的公共卫生问题。
