Differential Type I Interferon Signaling Is a Master Regulator of Susceptibility to Postinfluenza Bacterial Superinfection.
Differential Type I Interferon Signaling Is a Master Regulator of Susceptibility to Postinfluenza Bacterial Superinfection.
复制标题
DOI：
10.1128/mbio.00506-16
复制
发表时间：
2016-05-03
期刊：
影响因子：
6.4
通讯作者：
Rynda-Apple A
中科院分区：
文献类型：
--
作者：
Shepardson KM;Larson K;Morton RV;Prigge JR;Schmidt EE;Huber VC;Rynda-Apple A
细菌重复感染是流感大流行和流行期间死亡的主要原因。I型干扰素（IFN）信号传导有助于增加小鼠在甲型流感病毒（IAV）感染后第7天左右对细菌重复感染的易感性。在这里，我们证明了IAV感染后第3天耐甲氧西林金黄色葡萄球菌（MRSA）的敏感性降低，我们以前报道是由于白细胞介素-13（IL-13）/IFN-γ应答，也依赖于I型IFN信号传导及其随后的保护性IL-13产生的要求。我们发现，通过使用封闭抗体，IAV感染后第3天对MRSA的敏感性降低是IFN-β依赖性的，而第7天对MRSA的敏感性增加是IFN-α依赖性的。IAV感染早期的IFN-β信号是MRSA清除所必需的，而感染晚期的IFN-α信号则不是，尽管它确实介导了当时对MRSA的易感性增加。在IAV感染后第3天观察到的易感性降低需要CD 11 c+和Ly 6 G+细胞中的I型IFN受体（IFNAR）信号传导。在IFNAR信号传导被阻断或缺失的小鼠中Ly 6 G+细胞的耗尽表明Ly 6 G+细胞负责IAV感染后第7天对MRSA双重感染的IFNAR信号传导依赖性易感性。因此，在IAV感染期间，I型IFN信号传导的时间差异在第3天增加了CD 11 c+和Ly 6 G+细胞的杀菌活性，并在第7天降低了Ly 6 G+细胞的效应功能。IFN-β（第3天）和IFN-α（第7天）通过相同的IFNAR信号转导诱导的时间差异结果导致IAV感染后3天和7天对MRSA的敏感性差异。美国每年约有114，000例住院治疗和40，000例死亡与甲型流感病毒（IAV）感染有关。通常，这些死亡是由于社区获得性革兰氏阳性细菌物种，其中许多显示出对抗生素治疗的耐药性增加。根据病毒或细菌表达的毒力因子，可能出现严重的并发症，包括胸膜旁脓胸和坏死性肺炎。不幸的是，我们无法控制这些毒力因子的表达，使宿主反应成为治疗干预的合理目标。此外，病毒，宿主和细菌之间的相互作用，加剧IAV相关的发病率和死亡率在很大程度上是未知的。在这里，我们表明，I型干扰素（IFN）的表达可以调节耐甲氧西林金黄色葡萄球菌（MRSA）感染的易感性，IFN-β降低宿主对MRSA感染的易感性，而IFN-α增加易感性。我们的数据表明，设计用于在IAV感染后第7天左右增加IFN-β和/或抑制IFN-α产生的治疗可以降低对致命性双重感染的易感性。
Bacterial superinfections are a primary cause of death during influenza pandemics and epidemics. Type I interferon (IFN) signaling contributes to increased susceptibility of mice to bacterial superinfection around day 7 post-influenza A virus (IAV) infection. Here we demonstrate that the reduced susceptibility to methicillin-resistant Staphylococcus aureus (MRSA) at day 3 post-IAV infection, which we previously reported was due to interleukin-13 (IL-13)/IFN-γ responses, is also dependent on type I IFN signaling and its subsequent requirement for protective IL-13 production. We found, through utilization of blocking antibodies, that reduced susceptibility to MRSA at day 3 post-IAV infection was IFN-β dependent, whereas the increased susceptibility at day 7 was IFN-α dependent. IFN-β signaling early in IAV infection was required for MRSA clearance, whereas IFN-α signaling late in infection was not, though it did mediate increased susceptibility to MRSA at that time. Type I IFN receptor (IFNAR) signaling in CD11c+ and Ly6G+ cells was required for the observed reduced susceptibility at day 3 post-IAV infection. Depletion of Ly6G+ cells in mice in which IFNAR signaling was either blocked or deleted indicated that Ly6G+ cells were responsible for the IFNAR signaling-dependent susceptibility to MRSA superinfection at day 7 post-IAV infection. Thus, during IAV infection, the temporal differences in type I IFN signaling increased bactericidal activity of both CD11c+ and Ly6G+ cells at day 3 and reduced effector function of Ly6G+ cells at day 7. The temporal differential outcomes induced by IFN-β (day 3) and IFN-α (day 7) signaling through the same IFNAR resulted in differential susceptibility to MRSA at 3 and 7 days post-IAV infection. Approximately 114,000 hospitalizations and 40,000 annual deaths in the United States are associated with influenza A virus (IAV) infections. Frequently, these deaths are due to community-acquired Gram-positive bacterial species, many of which show increasing resistance to antibiotic therapy. Severe complications, including parapneumonic empyema and necrotizing pneumonia, can arise, depending on virulence factors expressed by either the virus or bacteria. Unfortunately, we are unable to control the expression of these virulence factors, making host responses a logical target for therapeutic interventions. Moreover, interactions between virus, host, and bacteria that exacerbate IAV-related morbidities and mortalities are largely unknown. Here, we show that type I interferon (IFN) expression can modulate susceptibility to methicillin-resistant Staphylococcus aureus (MRSA) infection, with IFN-β reducing host susceptibility to MRSA infection while IFN-α increases susceptibility. Our data indicate that treatments designed to augment IFN-β and/or inhibit IFN-α production around day 7 post-IAV infection could reduce susceptibility to deadly superinfections.