Streptolysins are the primary inflammasome activators in macrophages during Streptococcus pyogenes infection
Streptolysins are the primary inflammasome activators in macrophages during Streptococcus pyogenes infection
复制标题
DOI：
10.1111/imcb.12499
复制
发表时间：
2021-09-18
影响因子：
4
通讯作者：
Walker, Mark J.
中科院分区：
文献类型：
--
作者：
Richter, Johanna;Monteleone, Mercedes M.;Walker, Mark J.
A组链球菌（GAS）是一种革兰氏阳性细菌病原体，其在人类中引起一系列感染性疾病。越来越多的临床证据表明，促炎性白细胞介素（IL）-1 β信号在GAS疾病进展中起着重要作用。宿主通过胞质炎性体途径调节IL-1 β的产生和分泌。含有NLR家族pyrin结构域的3（NLRP 3）炎性体复合物的活化需要两个信号：刺激编码炎性体途径组分的基因的转录增加的引发信号，和诱导炎性体复合物的组装的活化信号。在这里，我们表明，气体衍生的脂磷壁酸可以提供一个引发信号NLRP 3炎性小体激活。由于只有少数GAS衍生的蛋白质与炎性小体依赖性IL-1 β信号传导相关，我们研究了可能在激活炎性小体途径中发挥作用的新候选物，通过用一组同基因GAS突变株感染小鼠骨髓衍生的巨噬细胞和人THP-1巨噬细胞样细胞。我们发现溶细胞素链球菌溶血素O（SLO）和链球菌溶血素S是增殖对数期GAS中IL-1 β释放的主要驱动因素。使用重组SLO的突变形式，我们证实宿主细胞膜上的细菌孔形成是炎性小体激活所需的关键机制。我们的研究结果表明，链球菌溶血素是气体诱导的炎症的主要决定因素，并提出了一个有吸引力的治疗干预的目标。
Group A Streptococcus (GAS) is a Gram-positive bacterial pathogen that causes an array of infectious diseases in humans. Accumulating clinical evidence suggests that proinflammatory interleukin (IL)-1 beta signaling plays an important role in GAS disease progression. The host regulates the production and secretion of IL-1 beta via the cytosolic inflammasome pathway. Activation of the NLR family pyrin domain-containing 3 (NLRP3) inflammasome complex requires two signals: a priming signal that stimulates increased transcription of genes encoding the components of the inflammasome pathway, and an activating signal that induces assembly of the inflammasome complex. Here we show that GAS-derived lipoteichoic acid can provide a priming signal for NLRP3 inflammasome activation. As only few GAS-derived proteins have been associated with inflammasome-dependent IL-1 beta signaling, we investigated novel candidates that might play a role in activating the inflammasome pathway by infecting mouse bone marrow-derived macrophages and human THP-1 macrophage-like cells with a panel of isogenic GAS mutant strains. We found that the cytolysins streptolysin O (SLO) and streptolysin S are the main drivers of IL-1 beta release in proliferating logarithmic phase GAS. Using a mutant form of recombinant SLO, we confirmed that bacterial pore formation on host cell membranes is a key mechanism required for inflammasome activation. Our results suggest that streptolysins are major determinants of GAS-induced inflammation and present an attractive target for therapeutic intervention.