Immunology Section, Department of Experimental Medical Sciences, Lund University, Lund, Sweden.
Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, United States.
Front Immunol. 2019 Jun 18;10:1385. doi: 10.3389/fimmu.2019.01385. eCollection 2019.
The common human pathogen Group A (GAS) causes superficial as well as invasive, life-threatening diseases. An increase in the occurrence of invasive GAS infection by strains of the M1 and M89 serotypes has been correlated with increased expression of the genetically and functionally linked virulence factors streptolysin O (SLO) and β-NAD-glycohydrolase (NADase). NADase affects host cells differently depending on its location: its SLO-dependent translocation into the cytosol can lead to cell death through β-NAD depletion, while extracellularly located NADase inhibits IL-1β release downstream of Nlrp3 inflammasome activation. In this study, we use a macrophage infection model to investigate the NADase-dependent inhibition of IL-1β release. We show that bacteria expressing a functional NADase evade P2X7 activation, while infection with a NADase-deficient GAS strain leads to a P2X7-mediated increase in IL-1β. Further, our data indicate that in the absence of NADase, IL-1β is released through both P2X7-dependent and -independent pathways, although the precise mechanisms of how this occur are still unclear. This study adds information about the mechanism by which NADase regulates inflammasome-dependent IL-1β release, which may in part explain why increased NADase expression correlates with bacterial virulence.
人类病原体 A 组链球菌（GAS）可引起浅表和侵袭性、危及生命的疾病。M1 和 M89 血清型侵袭性 GAS 感染菌株的发生率增加与遗传和功能上相关的毒力因子链球菌溶血素 O（SLO）和 β-NAD-糖基水解酶（NADase）表达增加有关。NADase 根据其位置的不同而对宿主细胞产生不同的影响：其 SLO 依赖性易位到细胞质可通过 β-NAD 耗竭导致细胞死亡，而细胞外定位的 NADase 可抑制 Nlrp3 炎性小体激活下游的 IL-1β 释放。在本研究中，我们使用巨噬细胞感染模型来研究 NADase 依赖性的 IL-1β 释放抑制。我们表明，表达功能性 NADase 的细菌逃避了 P2X7 的激活，而感染 NADase 缺陷型 GAS 菌株则导致 P2X7 介导的 IL-1β 增加。此外，我们的数据表明，在没有 NADase 的情况下，IL-1β 通过 P2X7 依赖性和非依赖性途径释放，尽管其确切机制仍不清楚。本研究增加了关于 NADase 调节炎性小体依赖性 IL-1β 释放的机制的信息，这可能部分解释了为什么 NADase 表达增加与细菌毒力相关。
