Delaney Martha A, Hartigh Andreas den, Carpentier Samuel J, Birkland Timothy P, Knowles Donald P, Cookson Brad T, Frevert Charles W
Departments of Comparative Medicine and Pathology, and the Comparative Pathology Program, 7284University of Washington, Seattle, WA.
Current address: Martha A. Delaney, Zoological Pathology Program, University of Illinois, Brookfield, IL, USA.
Vet Pathol. 2021 Jul;58(4):624-642. doi: 10.1177/0300985820981369. Epub 2020 Dec 28.
, a highly adapted obligate intracellular bacterial pathogen and the cause of the zoonosis Q fever, is a reemerging public health threat. employs a Type IV secretion system (T4SS) to establish and maintain its intracellular niche and modulate host immune responses including the inhibition of apoptosis. Interactions between and caspase-1-mediated inflammasomes are not fully elucidated. This study confirms that does not activate caspase-1 during infection of mouse macrophages in vitro. -infected cells did not develop NLRP3 and ASC foci indicating its ability to avoid cytosolic detection. is unable to inhibit the pyroptosis and IL-1β secretion that is induced by potent inflammasome stimuli but rather enhances these caspase-1-mediated effects. We found that upregulates pro-IL-1β and robustly primes NLRP3 inflammasomes via TLR2 and MyD88 signaling. As for wildtype , T4SS-deficient mutants primed and potentiated NLRP3 inflammasomes. An in vivo model of pulmonary infection in C57BL/6 mice was developed. Mice deficient in NLRP3 or caspase-1 were like wildtype mice in the development and resolution of splenomegaly due to red pulp hyperplasia, and histologic lesions and macrophage kinetics, but had slightly higher pulmonary bacterial burdens at the greatest measured time point. Together these findings indicate that primes but avoids cytosolic detection by NLRP3 inflammasomes, which are not required for the clinical resistance of C57BL/6 mice. Determining mechanisms employed by to avoid cytosolic detection via NLRP3 inflammasomes will be beneficial to the development of preventative and interventional therapies for Q fever.
柯克斯体是一种高度适应的专性细胞内细菌病原体，是人畜共患病Q热的病原体，是一种重新出现的公共卫生威胁。柯克斯体利用IV型分泌系统（T4SS）来建立和维持其细胞内生态位，并调节宿主免疫反应，包括抑制细胞凋亡。柯克斯体与半胱天冬酶-1介导的炎性小体之间的相互作用尚未完全阐明。本研究证实，柯克斯体在体外感染小鼠巨噬细胞期间不会激活半胱天冬酶-1。感染柯克斯体的细胞未形成NLRP3和ASC病灶，表明其具有避免胞质检测的能力。柯克斯体无法抑制由强效炎性小体刺激诱导的细胞焦亡和IL-1β分泌，反而增强了这些半胱天冬酶-1介导的效应。我们发现，柯克斯体通过TLR2和MyD88信号上调前体IL-1β并强力启动NLRP3炎性小体。至于野生型柯克斯体，缺乏T4SS的突变体启动并增强了NLRP3炎性小体。建立了C57BL/6小鼠肺部感染的体内模型。缺乏NLRP3或半胱天冬酶-1的小鼠在因红髓增生导致的脾肿大的发展和消退、组织学病变和巨噬细胞动力学方面与野生型小鼠相似，但在最大测量时间点的肺部细菌载量略高。这些发现共同表明柯克斯体启动但避免被NLRP3炎性小体进行胞质检测，而NLRP3炎性小体对于C57BL/6小鼠的临床抵抗力并非必需。确定柯克斯体通过NLRP3炎性小体避免胞质检测所采用的机制将有利于开发Q热的预防和干预疗法。
