Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
Metabolomics Australia, The Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, Australia.
Infect Immun. 2020 May 20;88(6). doi: 10.1128/IAI.00913-19.
The zoonotic bacterial pathogen is the causative agent of Q fever, a febrile illness which can cause a serious chronic infection. is a unique intracellular bacterium which replicates within host lysosome-derived vacuoles. The ability of to replicate within this normally hostile compartment is dependent on the activity of the Dot/Icm type 4B secretion system. In a previous study, a transposon mutagenesis screen suggested that the disruption of the gene encoding the novel protein CBU2072 rendered incapable of intracellular replication. This protein, subsequently named EirA (ssential for ntracellular eplication A), is indispensable for intracellular replication and virulence, as demonstrated by infection of human cell lines and infection of The putative N-terminal signal peptide is essential for protein function but is not required for localization of EirA to the bacterial inner membrane compartment and axenic culture supernatant. In the absence of EirA, remains viable but nonreplicative within the host phagolysosome, as coinfection with expressing native EirA rescues the replicative defect in the mutant strain. In addition, while the bacterial ultrastructure appears to be intact, there is an altered metabolic profile shift in the absence of EirA, suggesting that EirA may impact overall metabolism. Most strikingly, in the absence of EirA, Dot/Icm effector translocation was inhibited even when EirA-deficient replicated in the wild type (WT)-supported containing vacuoles. EirA may therefore have a novel role in the control of Dot/Icm activity and represent an important new therapeutic target.
动物源细菌病原体 是 Q 热的病原体，Q 热是一种发热疾病，可导致严重的慢性感染。 是一种独特的细胞内细菌，在宿主溶酶体衍生的空泡内复制。 能够在这个通常敌对的隔室中复制取决于 Dot/Icm 型 4B 分泌系统的活性。在之前的一项研究中，转座子诱变筛选表明，破坏编码新型蛋白 CBU2072 的基因使 无法进行细胞内复制。该蛋白随后被命名为 EirA（细胞内复制必需 A），对于细胞内复制和毒力是不可或缺的，这在人细胞系感染和 感染 中得到了证实。推测的 N 端信号肽对于蛋白功能是必需的，但对于 EirA 定位到细菌内膜隔室和无细胞培养上清液是不需要的。在没有 EirA 的情况下， 仍然在宿主吞噬溶酶体内存活但无法复制，因为与表达天然 EirA 的 共感染可挽救突变株的复制缺陷。此外，虽然细菌的超微结构似乎完整，但在没有 EirA 的情况下代谢谱发生了改变，表明 EirA 可能影响整体代谢。最引人注目的是，在没有 EirA 的情况下，即使在野生型（WT）支持的含有空泡中复制，Dot/Icm 效应物的易位也被抑制。因此，EirA 可能在控制 Dot/Icm 活性方面具有新的作用，并代表一个重要的新治疗靶点。
