Type I IFN Signaling Is Essential for Preventing IFN-γ Hyperproduction and Subsequent Deterioration of Antibacterial Immunity during Postinfluenza Pneumococcal Infection.
Type I IFN Signaling Is Essential for Preventing IFN-γ Hyperproduction and Subsequent Deterioration of Antibacterial Immunity during Postinfluenza Pneumococcal Infection.
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I型IFN信号传导对于预防流感后肺炎球菌感染期间IFN-γ过度产生和随后的抗菌免疫力恶化至关重要。
DOI：
10.4049/jimmunol.2101135
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发表时间：
2022-07-01
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影响因子：
--
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中科院分区：
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流感后细菌性肺炎是人类住院和死亡的重要原因。这种病毒和细菌协同作用的机制仍然不完全清楚。最近的证据表明，流感诱导的干扰素（IFN），特别是I型IFN（IFN-I）和IFN-γ，抑制抗菌防御。在这里，我们研究了IFN-I和IFN-γ途径在流感诱导的肺炎链球菌感染易感性中的相对重要性和相互作用。使用基因缺陷小鼠模型以及体内阻断抗体，我们发现IFN-I和IFN-γ信号通路均有助于抗菌免疫的初始抑制;然而，IFN-γ在疾病恶化中起主导作用，与TNF-α产生增加和肺泡巨噬细胞（AM）消耗有关。我们以前已经表明，IFN-γ损害AM抗菌功能，从而急性细菌清除。本研究的结果表明，IFN-γ信号传导也会在流感/S进展期间损害AM活力和αβ T细胞募集。肺炎合并感染。对IFN-γ不敏感的巨噬细胞（MIIG）小鼠在单核吞噬细胞中表达显性阴性突变型IFN-γ受体。有趣的是，MIIG小鼠表现出显着改善的恢复和生存从合并感染，尽管延迟细菌清除。重要的是，我们证明了IFN-I受体信号传导对于预防流感后肺炎球菌肺炎进展期间IFN-γ过度产生和动物死亡至关重要。
Post-influenza bacterial pneumonia is a significant cause of hospitalization and death in humans. The mechanisms underlying this viral and bacterial synergy remain incompletely understood. Recent evidence indicates that influenza-induced interferons (IFN), particularly type I IFN (IFN-I) and IFN-γ, suppress antibacterial defenses. Here we have investigated the relative importance and interplay of IFN-I and IFN-γ pathways in influenza-induced susceptibility to Streptococcus pneumoniae infection. Using gene-deficient mouse models as well as in vivo blocking antibodies, we show that both IFN-I and IFN-γ signaling pathways contribute to the initial suppression of antibacterial immunity; however, IFN-γ plays a dominant role in the disease deterioration, in association with increased TNF-α production and alveolar macrophage (AM) depletion. We have previously shown that IFN-γ impairs AM antibacterial function and thereby acute bacterial clearance. The findings in this study indicate that IFN-γ signaling also impairs AM viability and αβ T cell recruitment during the progression of influenza/S. pneumoniae coinfection. Macrophages insensitive to IFN-γ (MIIG) mice express a dominant negative mutant IFN-γ receptor in mononuclear phagocytes. Interestingly, MIIG mice exhibited significantly improved recovery and survival from coinfection, despite delayed bacterial clearance. Importantly, we demonstrate that IFN-I receptor signaling is essential for preventing IFN-γ hyperproduction and animal death during the progression of post-influenza pneumococcal pneumonia.
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