Sequential targeting of interferon pathways for increased host resistance to bacterial superinfection during influenza.
Sequential targeting of interferon pathways for increased host resistance to bacterial superinfection during influenza.
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DOI：
10.1371/journal.ppat.1009405
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发表时间：
2021-03
期刊：
影响因子：
6.7
通讯作者：
Metzger DW
中科院分区：
文献类型：
--
作者：
Barman TK;Racine R;Bonin JL;Califano D;Salmon SL;Metzger DW
细菌混合感染是流感的主要临床并发症。宿主来源的干扰素(干扰素)增加了流感后细菌感染的易感性，但I型和II型干扰素的相对作用仍不清楚。我们使用了新的小鼠混合感染模型，其中定植肺炎球菌接种到上呼吸道；随后的亚致死性流感病毒感染导致细菌进入肺部并介导致命疾病。与野生型小鼠或仅缺乏一条途径的小鼠相比，缺乏两条干扰素途径的小鼠在肺炎球菌流感病毒重叠感染后表现出最少的肺组织损伤和死亡率。I型和II型干扰素通路的治疗性中和同样为合并感染的野生型小鼠提供了最佳保护。最有效的治疗方案是在合并感染期间早期交错中和I型干扰素途径，然后中和II型干扰素，这与这些IFN在重叠感染期间的表达和已报道的活性一致。这些结果首次直接比较了I型和II型干扰素在重叠感染期间的活性，并为治疗流感期间继发性细菌感染的潜在宿主定向靶点提供了新的见解。细菌混合感染是流感的一种常见且具有挑战性的临床并发症。I型和II型干扰素途径增加了流感和肺炎球菌混合感染的易感性，导致肺部病理和死亡率增加。然而，I型和II型干扰素的相对重要性仍不清楚。我们使用了两种新的小鼠混合感染模型，在这两种模型中，肺炎球菌接种到上呼吸道，两天后感染流感病毒。病毒的混合感染引起了干扰素依赖的炎症，促进了定植细菌向肺部的传播，随后导致组织损伤和死亡。在这个肺炎球菌-流感病毒重叠感染模型中，与野生型和只缺乏一条途径的小鼠相比，缺乏I型和II型干扰素途径的小鼠表现出最小的肺部病理，并提高了存活率。I型和II型干扰素通路的治疗性中和同样为重叠感染的野生型小鼠提供了最佳保护。最有效的治疗方案包括在合并感染期间早期中和I型干扰素途径，结合后来中和II型干扰素途径。这些结果为管理细菌-病毒双重感染的潜在宿主导向疗法提供了新的见解。
Bacterial co-infections represent a major clinical complication of influenza. Host-derived interferon (IFN) increases susceptibility to bacterial infections following influenza, but the relative roles of type-I versus type-II IFN remain poorly understood. We have used novel mouse models of co-infection in which colonizing pneumococci were inoculated into the upper respiratory tract; subsequent sublethal influenza virus infection caused the bacteria to enter the lungs and mediate lethal disease. Compared to wild-type mice or mice deficient in only one pathway, mice lacking both IFN pathways demonstrated the least amount of lung tissue damage and mortality following pneumococcal-influenza virus superinfection. Therapeutic neutralization of both type-I and type-II IFN pathways similarly provided optimal protection to co-infected wild-type mice. The most effective treatment regimen was staggered neutralization of the type-I IFN pathway early during co-infection combined with later neutralization of type-II IFN, which was consistent with the expression and reported activities of these IFNs during superinfection. These results are the first to directly compare the activities of type-I and type-II IFN during superinfection and provide new insights into potential host-directed targets for treatment of secondary bacterial infections during influenza. Bacterial co-infections represent a common and challenging clinical complication of influenza. Type-I and type-II interferon (IFN) pathways enhance susceptibility to influenza-pneumococcal co-infection, leading to increased lung pathology and mortality. However, the comparative importance of type-I versus type-II IFN remains unclear. We have used two novel mouse models of co-infection in which pneumococci were inoculated into the upper respiratory tract followed two days later by influenza virus infection. Virus co-infection caused IFN-dependent inflammation that facilitated spreading of the colonizing bacteria into the lungs, followed by tissue damage and death. In this pneumococcal-influenza virus superinfection model, mice lacking both type-I and type-II IFN pathways demonstrated minimal lung pathology and increased survival compared to wild-type mice and mice deficient in only one pathway. Therapeutic neutralization of both type-I and type-II IFN pathways similarly provided optimal protection to superinfected wild-type mice. The most effective treatment regimen involved neutralization of the type-I IFN pathway early during co-infection combined with later neutralization of the type-II IFN pathway. These results provide new insights into potential host-directed therapy for management of bacterial-viral superinfections.
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影响因子：
8
作者：
Califano D;Furuya Y;Roberts S;Avram D;McKenzie ANJ;Metzger DW
通讯作者：
Metzger DW
DOI：
10.1086/591708
发表时间：
2008-10-01
期刊：
The Journal of infectious diseases
影响因子：
--
作者：
Morens DM;Taubenberger JK;Fauci AS
通讯作者：
Fauci AS
影响因子：
2.6
作者：
Do Thi Thu Hang;Choi, Eun-Jin;Shin, Yeun-Kyung
通讯作者：
Shin, Yeun-Kyung
影响因子：
5.8
作者：
Koehler, Jens;Breitbach, Katrin;Steinmetz, Ivo
通讯作者：
Steinmetz, Ivo
影响因子：
30.5
作者：
Jochems SP;Marcon F;Carniel BF;Holloway M;Mitsi E;Smith E;Gritzfeld JF;Solórzano C;Reiné J;Pojar S;Nikolaou E;German EL;Hyder-Wright A;Hill H;Hales C;de Steenhuijsen Piters WAA;Bogaert D;Adler H;Zaidi S;Connor V;Gordon SB;Rylance J;Nakaya HI;Ferreira DM
通讯作者：
Ferreira DM