Tran Cuong J, Zubair-Nizami Zahra, Langohr Ingeborg M, Welch Matthew D
Division of Infectious Disease and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, California, USA.
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California, USA.
mBio. 2025 Feb 5;16(2):e0256324. doi: 10.1128/mbio.02563-24. Epub 2025 Jan 17.
is an obligate intracellular, tick-borne bacterial pathogen that can cause eschar-associated rickettsiosis in humans. invades host cells, escapes from vacuoles into the cytosol, and undergoes two independent modes of actin-based motility mediated by effectors RickA or Sca2. Actin-based motility of enables bacteria to enter protrusions of the host cell plasma membrane that are engulfed by neighboring host cells. However, whether and how RickA and Sca2 independently contribute to cell-to-cell spread or pathogenicity has been unclear. Using live cell imaging of ::Tn and ::Tn mutants, we discovered both RickA and Sca2 contribute to different modes of cell-to-cell spread. Compared with Sca2-spread, RickA-spread involves the formation of longer protrusions that exhibit larger fluctuations in length and take a longer time to be engulfed into neighboring cells. We further compared the roles of RickA and Sca2 following intradermal (i.d.) infection of ; mice carrying knockout mutations in the genes encoding the receptors for IFN-I () and IFN-γ (), which exhibit eschars and succumb to infection with wild-type (WT) . We observed that RickA is important for severe eschar formation, whereas Sca2 contributes to larger foci of infection in the skin and dissemination from the skin to the internal organs. Our results suggest that actin-based motility effectors RickA and Sca2 drive two distinct forms of cell-to-cell spread and contribute differently to pathogenicity in the mammalian host.IMPORTANCE, a bacterium in the spotted fever group of species, can be transmitted from ticks to humans, leading to symptoms including fever, rash, muscle aches, and a lesion at the site of the tick bite. During infection, bacteria invade cells within the animal host, proliferate in the host cell's cytosol, move using a process called actin-based motility, and spread to neighboring host cells. is unusual in having two bacterial proteins that mediate actin-based motility. The significance of our research is to reveal that each of these bacterial actin-based motility proteins contributes differently to spread between cells and to the signs of infection in a mouse model of spotted fever disease. Our results are important for understanding the contribution of actin-based motility to mammalian infection by as well as to infection by other bacterial and viral pathogens that require this process to spread between cells and cause disease.
是一种专性细胞内、蜱传播的细菌病原体，可导致人类出现与焦痂相关的立克次体病。它侵入宿主细胞，从液泡逃逸到细胞质中，并通过效应蛋白RickA或Sca2介导经历两种独立的基于肌动蛋白的运动模式。基于肌动蛋白的运动使细菌能够进入宿主细胞质膜的突起，这些突起会被相邻的宿主细胞吞噬。然而，RickA和Sca2是否以及如何独立促进细胞间传播或致病性尚不清楚。通过对::Tn和::Tn突变体进行活细胞成像，我们发现RickA和Sca2都有助于不同模式的细胞间传播。与Sca2介导的传播相比，RickA介导的传播涉及形成更长的突起，这些突起在长度上表现出更大的波动，并且需要更长的时间才能被相邻细胞吞噬。我们进一步比较了在皮内（i.d.）感染后RickA和Sca2的作用；携带编码I型干扰素（）和γ干扰素（）受体的基因敲除突变的小鼠，这些小鼠会出现焦痂并死于野生型（WT）感染。我们观察到RickA对严重焦痂形成很重要，而Sca2有助于皮肤中更大的感染灶以及从皮肤扩散到内部器官。我们的结果表明，基于肌动蛋白的运动效应蛋白RickA和Sca2驱动两种不同形式的细胞间传播，并对哺乳动物宿主的致病性有不同贡献。重要性，是斑点热群物种中的一种细菌，可从蜱传播给人类，导致包括发热、皮疹、肌肉疼痛以及蜱叮咬部位出现病变等症状。在感染期间，细菌侵入动物宿主体内的细胞，在宿主细胞的细胞质中增殖，利用一种称为基于肌动蛋白的运动过程移动，并传播到相邻的宿主细胞。不同寻常的是，它有两种介导基于肌动蛋白运动的细菌蛋白。我们研究的意义在于揭示这些基于细菌肌动蛋白的运动蛋白中的每一种对细胞间传播以及斑点热疾病小鼠模型中的感染迹象都有不同的贡献。我们的结果对于理解基于肌动蛋白的运动对感染哺乳动物的贡献以及对其他需要此过程在细胞间传播并导致疾病的细菌和病毒病原体的感染都很重要。
