Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA.
JCI Insight. 2018 Apr 5;3(7). doi: 10.1172/jci.insight.97470.
Secondary bacterial respiratory infections are commonly associated with both acute and chronic lung injury. Influenza complicated by bacterial pneumonia is an effective model to study host defense during pulmonary superinfection due to its clinical relevance. Multiprotein inflammasomes are responsible for IL-1β production in response to infection and drive tissue inflammation. In this study, we examined the role of the inflammasome during viral/bacterial superinfection. We demonstrate that ASC-/- mice are protected from bacterial superinfection and produce sufficient quantities of IL-1β through an apoptosis-associated speck-like protein containing CARD (ASC) inflammasome-independent mechanism. Despite the production of IL-1β by ASC-/- mice in response to bacterial superinfection, these mice display decreased lung inflammation. A neutrophil elastase inhibitor blocked ASC inflammasome-independent production of IL-1β and the IL-1 receptor antagonist, anakinra, confirmed that IL-1 remains crucial to the clearance of bacteria during superinfection. Delayed inhibition of NLRP3 during influenza infection by MCC950 decreases bacterial burden during superinfection and leads to decreased inflammatory cytokine production. Collectively, our results demonstrate that ASC augments the clearance of bacteria, but can also contribute to inflammation and mortality. ASC should be considered as a therapeutic target to decrease morbidity and mortality during bacterial superinfection.
继发细菌性呼吸道感染通常与急性和慢性肺损伤有关。流感合并细菌性肺炎是研究肺部继发感染时宿主防御的有效模型，因为它具有临床相关性。多蛋白炎症小体负责在感染时产生 IL-1β，并驱动组织炎症。在这项研究中，我们研究了炎症小体在病毒/细菌继发感染中的作用。我们证明 ASC-/- 小鼠通过凋亡相关斑点样蛋白包含 CARD (ASC) 炎症小体非依赖性机制免受细菌继发感染的保护，并产生足够量的 IL-1β。尽管 ASC-/- 小鼠在细菌继发感染时产生 IL-1β，但这些小鼠的肺部炎症减少。中性粒细胞弹性蛋白酶抑制剂阻断 ASC 炎症小体非依赖性产生的 IL-1β，IL-1 受体拮抗剂 anakinra 证实，IL-1 在继发感染期间清除细菌仍然至关重要。MCC950 在流感感染期间对 NLRP3 的延迟抑制可降低继发感染时的细菌负荷，并导致炎症细胞因子产生减少。综上所述，我们的结果表明 ASC 增强了细菌的清除，但也可能导致炎症和死亡。ASC 应被视为减少细菌继发感染发病率和死亡率的治疗靶点。
