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DotU and VgrG, core components of type VI secretion systems, are essential for Francisella LVS pathogenicity

机译:VI型分泌系统的核心成分DotU和VgrG对于弗朗西斯菌LVS致病性至关重要

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摘要

The Gram-negative bacterium Francisella tularensis causes tularemia, a disease which requires bacterial escape from phagosomes of infected macrophages. Once in the cytosol, the bacterium rapidly multiplies, inhibits activation of the inflammasome and ultimately causes death of the host cell. Of importance for these processes is a 33-kb gene cluster, the Francisella pathogenicity island (FPI), which is believed to encode a type VI secretion system (T6SS). In this study, we analyzed the role of the FPI-encoded proteins VgrG and DotU, which are conserved components of type VI secretion (T6S) clusters. We demonstrate that in F. tularensis LVS, VgrG was shown to form multimers, consistent with its suggested role as a trimeric membrane puncturing device in T6SSs, while the inner membrane protein DotU was shown to stabilize PdpB/IcmF, another T6SS core component. Upon infection of J774 cells, both Delta vgrG and Delta dotU mutants did not escape from phagosomes, and subsequently, did not multiply or cause cytopathogenicity. They also showed impaired activation of the inflammasome and marked attenuation in the mouse model. Moreover, all of the DotU-dependent functions investigated here required the presence of three residues that are essentially conserved among all DotU homologues. Thus, in agreement with a core function in T6S clusters, VgrG and DotU play key roles for modulation of the intracellular host response as well as for the virulence of F. tularensis.
机译:革兰氏阴性菌土拉弗朗西斯菌会引起tularemia,这是一种需要细菌从被感染的巨噬细胞吞噬体中逸出的疾病。一旦进入胞质溶胶,细菌就会迅速繁殖,抑制炎性体的活化,并最终导致宿主细胞死亡。对于这些过程而言,重要的是一个33 kb的基因簇,即弗朗西斯菌致病岛(FPI),据信该岛编码VI型分泌系统(T6SS)。在这项研究中,我们分析了FPI编码蛋白VgrG和DotU的作用,它们是VI型分泌(T6S)簇的保守组分。我们证明了在F. tularensis LVS中,VgrG被显示为形成多聚体,与其在T6SSs中作为三聚体膜穿刺装置的建议作用相一致,而内膜蛋白DotU被证明可稳定PdpB / IcmF,这是另一种T6SS核心成分。感染J774细胞后,Delta vgrG和Delta dotU突变体均未从吞噬体中逃逸,并且随后没有繁殖或引起细胞致病性。他们还显示了炎性小体的激活受损和小鼠模型的明显衰减。此外,这里研究的所有依赖于DotU的功能都需要存在三个在所有DotU同源物中基本保守的残基。因此,与T6S簇中的核心功能相一致,VgrG和DotU在调节细胞内宿主反应以及T.tumularensis的毒性中起着关键作用。

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