Genome-wide fitness profiling reveals adaptations required by Haemophilus in coinfection with influenza A virus in the murine lung.
Genome-wide fitness profiling reveals adaptations required by Haemophilus in coinfection with influenza A virus in the murine lung.
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全基因组适应性分析揭示了鼠肺中嗜血杆菌与甲型流感病毒共感染时所需的适应性。
DOI：
10.1073/pnas.1311217110
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发表时间：
2013
影响因子：
11.1
通讯作者：
Akerley,BrianJ
中科院分区：
文献类型：
--
作者：
Wong,SandyM;Bernui,Mariana;Shen,Hao;Akerley,BrianJ
细菌合并感染是甲型流感病毒（IAV）流行病发病和死亡的主要原因。流感嗜血杆菌通常在人上呼吸道定植而不引起疾病，但在感染IAV的个体中，它可引起使人衰弱或致命的继发性肺炎。在小鼠模型中的研究已经检测到了与易感性和病理学有关的免疫成分，但很少有研究检查了导致合并感染的细菌因素。我们对H.在与IAV共感染的小鼠模型中，流感病毒基因促进其适应性。应用转座子插入位点的直接高通量测序揭示了一个H.与单独细菌感染相比，流感病毒合并感染中的流感病毒突变体。在非病毒感染的小鼠中需要一组毒力基因，但在合并感染中则不需要，这与合并感染期间抗菌防御的缺陷一致。然而，在两种体内条件下所需的一组核心基因表明，许多细菌对抗宿主防御的措施对合并感染仍然至关重要。结果还揭示了共同感染所需的基因子集，而不是单独的细菌感染，包括铁硫簇调节基因iscR，这是抗氧化应激所需的。抗氧化蛋白Dps的过表达在突变体中恢复了抗氧化应激和在共同感染中的定殖能力。结果确定了IAV合并感染模型中所需的细菌应激和代谢适应，揭示了治疗或预防病毒感染后继发性细菌性肺炎的潜在目标。
Bacterial coinfection represents a major cause of morbidity and mortality in epidemics of influenza A virus (IAV). The bacteriumHaemophilus influenzaetypically colonizes the human upper respiratory tract without causing disease, and yet in individuals infected with IAV, it can cause debilitating or lethal secondary pneumonia. Studies in murine models have detected immune components involved in susceptibility and pathology, and yet few studies have examined bacterial factors contributing to coinfection. We conducted genome-wide profiling of theH. influenzaegenes that promote its fitness in a murine model of coinfection with IAV. Application of direct, high-throughput sequencing of transposon insertion sites revealed fitness phenotypes of a bank ofH. influenzaemutants in viral coinfection in comparison with bacterial infection alone. One set of virulence genes was required in nonvirally infected mice but not in coinfection, consistent with a defect in anti-bacterial defenses during coinfection. Nevertheless, a core set of genes required in both in vivo conditions indicated that many bacterial countermeasures against host defenses remain critical for coinfection. The results also revealed a subset of genes required in coinfection but not in bacterial infection alone, including the iron-sulfur cluster regulator gene,iscR, which was required for oxidative stress resistance. Overexpression of the antioxidant protein Dps in theiscRmutant restored oxidative stress resistance and ability to colonize in coinfection. The results identify bacterial stress and metabolic adaptations required in an IAV coinfection model, revealing potential targets for treatment or prevention of secondary bacterial pneumonia after viral infection.