Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA.
Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch, Galveston, Texas, USA.
Infect Immun. 2020 Mar 23;88(4). doi: 10.1128/IAI.00886-19.
Rickettsiae are cytosolically replicating, obligately intracellular bacteria causing human infections worldwide with potentially fatal outcomes. We previously showed that activates ASC inflammasome in macrophages. In the present study, host susceptibility of ASC inflammasome-deficient mice to was significantly greater than that of C57BL/6 (B6) controls and was accompanied by increased rickettsial loads in various organs. Impaired host control of in ASC mice was associated with dramatically reduced levels of interleukin 1β (IL-1β), IL-18, and gamma interferon (IFN-γ) in sera. The intracellular concentrations of in bone marrow-derived macrophages (BMMs) of TLR4 and ASC mice were significantly greater than those in BMMs of B6 controls, highlighting the important role of inflammasome and these molecules in controlling rickettsiae in macrophages. Compared to B6 BMMs, TLR4 BMMs failed to secrete a significant level of IL-1β and had reduced expression levels of pro-IL-1β in response to infection with , suggesting that rickettsiae activate ASC inflammasome via a Toll-like receptor 4 (TLR4)-dependent mechanism. Further mechanistic studies suggest that the lipopolysaccharide (LPS) purified from together with ATP stimulation led to cleavage of pro-caspase-1 and pro-IL-1β, resulting in TLR4-dependent secretion of IL-1β. Taken together, these observations indicate that activation of ASC inflammasome, most likely driven by interaction of TLR4 with rickettsial LPS, contributes to host protective immunity against These findings provide key insights into defining the interactions of rickettsiae with the host innate immune system.
立克次体是在细胞质中复制的、专性细胞内细菌，在全球范围内引起人类感染，并有潜在的致命后果。我们之前曾表明， 激活了巨噬细胞中的 ASC 炎症小体。在本研究中，ASC 炎症小体缺陷型小鼠对 的宿主易感性明显高于 C57BL/6（B6）对照小鼠，并且各种器官中的立克次体载量增加。在 ASC 小鼠中，宿主对立克次体的控制受损与血清中白细胞介素 1β（IL-1β）、IL-18 和γ干扰素（IFN-γ）水平显著降低有关。TLR4 和 ASC 小鼠骨髓来源的巨噬细胞（BMM）中的 细胞内浓度明显高于 B6 对照 BMM，这突出了炎症小体和这些分子在控制巨噬细胞中立克次体中的重要作用。与 B6 BMM 相比，TLR4 BMM 未能分泌出显著水平的 IL-1β，并且在感染 时 pro-IL-1β 的表达水平降低，这表明立克次体通过 Toll 样受体 4（TLR4）依赖性机制激活 ASC 炎症小体。进一步的机制研究表明，从 中纯化的脂多糖（LPS）与 ATP 刺激一起导致前胱天蛋白酶-1和前 IL-1β 的切割，导致 TLR4 依赖性 IL-1β 的分泌。综上所述，这些观察结果表明，ASC 炎症小体的激活，很可能是由 TLR4 与立克次体 LPS 的相互作用驱动的，有助于宿主对抗 的保护性免疫。这些发现为定义立克次体与宿主固有免疫系统的相互作用提供了重要的见解。
