Streptococcus pneumoniae is a common cause of post-influenza secondary bacterial infection, which results in excessive morbidity and mortality. Although 13-valent pneumococcal conjugate vaccine (PCV13) vaccination programs have decreased the incidence of pneumococcal pneumonia, PCV13 failed to prevent serotype 3 pneumococcal disease as effectively as other vaccine serotypes. We aimed to investigate the mechanisms underlying the co-pathogenesis of influenza virus and serotype 3 pneumococci. We carried out a genome-wide screening of a serotype 3 S. pneumoniae transposon insertion mutant library in a mouse model of coinfection with influenza A virus (IAV) to identify the bacterial factors required for this synergism. Direct, high-throughput sequencing of transposon insertion sites identified 24 genes required for both coinfection and bacterial infection alone. Targeted deletion of the putative aminotransferase (PA) gene decreased bacterial growth, which was restored by supplementation with methionine. The bacterial burden in a coinfection with the PA gene deletion mutant and IAV in the lung was lower than that in a coinfection with wild-type pneumococcus and IAV, but was significantly higher than that in an infection with the PA gene deletion mutant alone. These data suggest that IAV infection alters host metabolism to benefit pneumococcal fitness and confer higher susceptibility to pneumococcal infection. We further demonstrated that bacterial growth was increased by supplementation with methionine or IAV-infected mouse lung homogenates. The data indicates that modulation of host metabolism during IAV infection may serve as a potential therapeutic intervention against secondary bacterial infections caused by serotype 3 pneumococci during IAV outbreaks in the future.

中文翻译：

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肺炎链球菌与甲型流感病毒合并感染所需的细菌因素

肺炎链球菌是流感后继发细菌感染的常见原因，导致发病率和死亡率过高。尽管13价肺炎球菌结合疫苗（PCV13）疫苗接种计划降低了肺炎球菌肺炎的发病率，但PCV13未能像其他疫苗血清型那样有效地预防血清型3肺炎球菌疾病。我们的目的是研究流感病毒和血清型 3 肺炎球菌共同发病的机制。我们在甲型流感病毒（IAV）共感染小鼠模型中对血清型 3 肺炎链球菌转座子插入突变体库进行了全基因组筛选，以确定这种协同作用所需的细菌因子。对转座子插入位点进行直接高通量测序，鉴定出共感染和单独细菌感染所需的 24 个基因。假定的转氨酶（PA）基因的定向缺失会减少细菌生长，通过补充蛋氨酸可以恢复细菌生长。PA基因缺失突变体和IAV共感染肺内细菌负荷低于野生型肺炎球菌和IAV共感染，但显着高于单独感染PA基因缺失突变体。这些数据表明，IAV 感染改变宿主代谢，有利于肺炎球菌的健康，并提高对肺炎球菌感染的易感性。我们进一步证明，补充蛋氨酸或 IAV 感染的小鼠肺匀浆可以促进细菌生长。数据表明，在 IAV 感染期间调节宿主代谢可能成为未来 IAV 暴发期间针对血清型 3 肺炎球菌引起的继发性细菌感染的潜在治疗干预措施。