Virulent Coxiella burnetii pathotypes productively infect primary human alveolar macrophages.
Virulent Coxiella burnetii pathotypes productively infect primary human alveolar macrophages.
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DOI：
10.1111/cmi.12096
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发表时间：
2013-06
影响因子：
3.4
通讯作者：
Voth DE
中科院分区：
文献类型：
--
作者：
Graham JG;MacDonald LJ;Hussain SK;Sharma UM;Kurten RC;Voth DE
胞内细菌病原体伯纳氏克希菌是引起人类Q热的B类选择剂。在体内，伯氏梭菌以肺泡巨噬细胞为目标，其中病原体在溶酶体样寄生液泡（PV）中复制。在体外，伯纳氏杆菌感染多种培养细胞系，这些细胞系已被共同用于模拟病原体的感染周期。然而，已经观察到细胞对感染的反应存在差异，并且尚未很好地定义伯纳蒂胞杆菌分离物感染宿主细胞的毒性。由于肺泡巨噬细胞通常与疾病有关，因此我们建立了原代人肺泡巨噬细胞（hAMs）作为伯氏杆菌与宿主细胞相互作用的体外模型。尽管具有独特的PV特性，但伯纳蒂胞杆菌的病理类型，包括急性疾病和心内膜炎分离株，在ham中可以复制。每个分离物在大的、典型的PV和小的、不融合的液泡中复制，并且在无毒的伯纳氏梭菌PV中存在脂滴。有趣的是，小液泡的一个子集容纳了正在降解的单个生物体。ham中典型PV的形成和细菌的生长需要一个功能性的IV型分泌系统，这表明伯纳蒂梭菌分泌控制巨噬细胞功能的效应蛋白。无毒burnetii促进Akt和Erk1/2促生存激酶的持续激活以及应激相关p38的短期磷酸化。无毒生物也引发了强烈的早期促炎反应，其特征是TNF-α和IL-6的分泌增加，而有毒分离物则引起这些细胞因子的分泌大幅减少。在感染了无毒伯纳氏梭菌的ham中，IL-1β的前期和成熟水平均有相应的增加，而在感染了毒力分离株后，IL-1β的积累很少。最后，用IFN-γ治疗ham控制细胞内复制，支持这种抗菌损伤在宿主对伯氏梭菌的反应中的作用。总的来说，目前的结果表明，hAM模型是一个与人类疾病相关的平台，用于定义对伯纳蒂杆菌的新型先天免疫反应。
The intracellular bacterial pathogen Coxiella burnetii is a category B select agent that causes human Q fever. In vivo, C. burnetii targets alveolar macrophages wherein the pathogen replicates in a lysosome-like parasitophorous vacuole (PV). In vitro, C. burnetii infects a variety of cultured cell lines that have collectively been used to model the pathogen’s infectious cycle. However, differences in the cellular response to infection have been observed, and virulent C. burnetii isolate infection of host cells has not been well defined. Because alveolar macrophages are routinely implicated in disease, we established primary human alveolar macrophages (hAMs) as an in vitro model of C. burnetii-host cell interactions. C. burnetii pathotypes, including acute disease and endocarditis isolates, replicated in hAMs, albeit with unique PV properties. Each isolate replicated in large, typical PV and small, non-fused vacuoles, and lipid droplets were present in avirulent C. burnetii PV. Interestingly, a subset of small vacuoles harbored single organisms undergoing degradation. Prototypical PV formation and bacterial growth in hAMs required a functional type IV secretion system, indicating C. burnetii secretes effector proteins that control macrophage functions. Avirulent C. burnetii promoted sustained activation of Akt and Erk1/2 pro-survival kinases and short term phosphorylation of stress-related p38. Avirulent organisms also triggered a robust, early pro-inflammatory response characterized by increased secretion of TNF-α and IL-6, while virulent isolates elicited substantially reduced secretion of these cytokines. A corresponding increase in pro- and mature IL-1β occurred in hAMs infected with avirulent C. burnetii, while little accumulation was observed following infection with virulent isolates. Finally, treatment of hAMs with IFN-γ controlled intracellular replication, supporting a role for this antibacterial insult in the host response to C. burnetii. Collectively, the current results demonstrate the hAM model is a human disease-relevant platform for defining novel innate immune responses to C. burnetii.
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影响因子：
6.7
作者：
Carey KL;Newton HJ;Lührmann A;Roy CR
通讯作者：
Roy CR
影响因子：
6.4
作者：
Beare PA;Gilk SD;Larson CL;Hill J;Stead CM;Omsland A;Cockrell DC;Howe D;Voth DE;Heinzen RA
通讯作者：
Heinzen RA
影响因子：
7
作者：
Barker BR;Taxman DJ;Ting JP
通讯作者：
Ting JP
影响因子：
3.4
作者：
Howe, D;Melnicáková, J;Heinzen, RA
通讯作者：
Heinzen, RA
影响因子：
3.1
作者：
Hill, J.;Samuel, J. E.
通讯作者：
Samuel, J. E.