Tate Michelle D, Ong James D H, Dowling Jennifer K, McAuley Julie L, Robertson Avril B, Latz Eicke, Drummond Grant R, Cooper Matthew A, Hertzog Paul J, Mansell Ashley
Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.
Department of Molecular and Translational Sciences, Monash University, Clayton, Victoria, Australia.
Sci Rep. 2016 Jun 10;6:27912. doi: 10.1038/srep27912.
The inflammasome NLRP3 is activated by pathogen associated molecular patterns (PAMPs) during infection, including RNA and proteins from influenza A virus (IAV). However, chronic activation by danger associated molecular patterns (DAMPs) can be deleterious to the host. We show that blocking NLRP3 activation can be either protective or detrimental at different stages of lethal influenza A virus (IAV). Administration of the specific NLRP3 inhibitor MCC950 to mice from one day following IAV challenge resulted in hypersusceptibility to lethality. In contrast, delaying treatment with MCC950 until the height of disease (a more likely clinical scenario) significantly protected mice from severe and highly virulent IAV-induced disease. These findings identify for the first time that NLRP3 plays a detrimental role later in infection, contributing to IAV pathogenesis through increased cytokine production and lung cellular infiltrates. These studies also provide the first evidence identifying NLRP3 inhibition as a novel therapeutic target to reduce IAV disease severity.
炎性小体NLRP3在感染期间由病原体相关分子模式（PAMP）激活，包括来自甲型流感病毒（IAV）的RNA和蛋白质。然而，由危险相关分子模式（DAMP）引起的慢性激活可能对宿主有害。我们发现，在致死性甲型流感病毒（IAV）感染的不同阶段，阻断NLRP3激活可能具有保护作用或有害作用。在IAV攻击后一天给小鼠施用特异性NLRP3抑制剂MCC950会导致对致死性的易感性增加。相比之下，将MCC950治疗推迟到疾病高峰期（更可能出现的临床情况）可显著保护小鼠免受严重且高致病性IAV诱导的疾病。这些发现首次确定NLRP3在感染后期起有害作用，通过增加细胞因子产生和肺细胞浸润促进IAV发病机制。这些研究还提供了首个证据，确定NLRP3抑制作为降低IAV疾病严重程度的新型治疗靶点。
