Lambda Interferon Restructures the Nasal Microbiome and Increases Susceptibility to Staphylococcus aureus Superinfection.
Lambda Interferon Restructures the Nasal Microbiome and Increases Susceptibility to Staphylococcus aureus Superinfection.
复制标题
Lambda干扰素重组鼻微生物组，并增加对金黄色葡萄球菌超级感染的敏感性。
DOI：
10.1128/mbio.01939-15
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发表时间：
2016-02-09
期刊：
影响因子：
6.4
通讯作者：
Prince AS
中科院分区：
文献类型：
--
作者：
Planet PJ;Parker D;Cohen TS;Smith H;Leon JD;Ryan C;Hammer TJ;Fierer N;Chen EI;Prince AS
与流感病毒呼吸道感染相关的大部分发病率和死亡率是由于细菌与定植于上呼吸道的病原体如耐甲氧西林金黄色葡萄球菌（MRSA）和肺炎链球菌的共感染。对流感病毒的免疫应答的主要组成部分是I型和III型干扰素的产生。在这里，我们表明，对流感病毒感染的免疫反应会导致野生型（WT）小鼠上呼吸道微生物群的增加和重组，但在缺乏III型干扰素受体的Il 28 r-/-突变小鼠中则不然。缺乏IL-28受体的小鼠不能诱导STAT 1磷酸化及其调节因子SOCS 1的表达。Il 28 r −/−突变小鼠的鼻腔中白细胞介素-22（IL-22）以及Ngal和RegIIIγ的表达增加，鼻腔是吸入导致肺炎的微生物的来源。蛋白质组学分析揭示了几种细胞骨架蛋白的变化，这些蛋白有助于鼻上皮中的屏障功能，这可能有助于IL-28信号传导对微生物群的影响。IL-28信号传导在流感病毒感染后MRSA肺炎发病机制中的重要性得到了证实，因为流感病毒感染前或感染后经鼻定植的WT小鼠上呼吸道感染水平显著高于IL-28 r −/−突变小鼠，对MRSA肺炎的易感性也显著高于IL-28 r −/−突变小鼠。我们的研究结果表明，响应流感病毒感染的III型干扰素的激活在扩大上呼吸道微生物组和增加对下呼吸道感染的易感性方面具有重要作用。金黄色葡萄球菌和流感病毒是重要的呼吸道病原体，与这些生物体的合并感染与显著的发病率和死亡率相关。流感病毒增加对金黄色葡萄球菌感染的易感性的能力还不太清楚。我们在这里表明，流感病毒以III型干扰素依赖的方式导致上呼吸道微生物组的变化。缺乏III型干扰素受体的小鼠具有改变的STAT 1和IL-22信号传导。在共感染研究中，没有III型干扰素受体的小鼠的鼻金黄色葡萄球菌定植和随后的肺炎比感染的WT小鼠显著更少。这项工作表明，流感病毒诱导的III型干扰素有助于鼻腔定植和肺炎由于金黄色葡萄球菌重叠感染。
Much of the morbidity and mortality associated with influenza virus respiratory infection is due to bacterial coinfection with pathogens that colonize the upper respiratory tract such as methicillin-resistant Staphylococcus aureus (MRSA) and Streptococcus pneumoniae. A major component of the immune response to influenza virus is the production of type I and III interferons. Here we show that the immune response to infection with influenza virus causes an increase and restructuring of the upper respiratory microbiota in wild-type (WT) mice but not in Il28r−/− mutant mice lacking the receptor for type III interferon. Mice lacking the IL-28 receptor fail to induce STAT1 phosphorylation and expression of its regulator, SOCS1. Il28r−/− mutant mice have increased expression of interleukin-22 (IL-22), as well as Ngal and RegIIIγ, in the nasal cavity, the source of organisms that would be aspirated to cause pneumonia. Proteomic analysis reveals changes in several cytoskeletal proteins that contribute to barrier function in the nasal epithelium that may contribute to the effects of IL-28 signaling on the microbiota. The importance of the effects of IL-28 signaling in the pathogenesis of MRSA pneumonia after influenza virus infection was confirmed by showing that WT mice nasally colonized before or after influenza virus infection had significantly higher levels of infection in the upper airways, as well as significantly greater susceptibility to MRSA pneumonia than Il28r−/− mutant mice did. Our results suggest that activation of the type III interferon in response to influenza virus infection has a major effect in expanding the upper airway microbiome and increasing susceptibility to lower respiratory tract infection. S. aureus and influenza virus are important respiratory pathogens, and coinfection with these organisms is associated with significant morbidity and mortality. The ability of influenza virus to increase susceptibility to S. aureus infection is less well understood. We show here that influenza virus leads to a change in the upper airway microbiome in a type III interferon-dependent manner. Mice lacking the type III interferon receptor have altered STAT1 and IL-22 signaling. In coinfection studies, mice without the type III interferon receptor had significantly less nasal S. aureus colonization and subsequent pneumonia than infected WT mice did. This work demonstrates that type III interferons induced by influenza virus contribute to nasal colonization and pneumonia due to S. aureus superinfection.