Chaichana Panjaporn, Satapoomin Naphat, Kullapanich Chitrasak, Chuenklin Suthida, Mohammad Aisha, Inthawong Manutsanun, Ball Erin E, Burke Thomas P, Sunyakumthorn Piyanate, Salje Jeanne
Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom.
Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
PLoS Pathog. 2025 Jun 30;21(6):e1012833. doi: 10.1371/journal.ppat.1012833. eCollection 2025 Jun.
Orientia tsutsugamushi is an obligate intracellular bacterium found in Leptotrombidium mites that causes the human disease scrub typhus. A distinguishing feature of O. tsutsugamushi is its extensive strain diversity, yet differences in virulence between strains are not well defined nor well understood. We sought to determine the bacterial drivers of pathogenicity by comparing seven strains using murine infections combined with epidemiological human data to rank each strain in terms of relative virulence. Murine cytokine expression data revealed that the two most virulent strains, Ikeda and Kato, induced higher levels of IL-6, IL-10, IFN-γ and MCP-1 than other strains, consistent with increased levels of these cytokines in patients with severe scrub typhus. We sought to identify the mechanistic basis of the observed differential virulence between strains by comparing their genomes, in vitro growth properties and cytokine/chemokine induction in host cells. We found that there was no single gene or gene group that correlated with virulence, and no clear pattern of in vitro growth rate that predicted disease. However, microscopy-based analysis of the intracellular infection cycle revealed that the only fully avirulent strain in our study, TA686, differed from all the virulent strains in its subcellular localisation and expression of its surface protein ScaC. This leads us to a model whereby drivers of pathogenicity in Orientia tsutsugamushi are distributed throughout the genome, likely in the large and varying arsenal of effector proteins encoded by different strains, and that these interact in complex ways to induce differing immune responses and thus differing disease outcomes in mammalian hosts.
恙虫病东方体是一种专性细胞内细菌，存在于恙螨中，可引起人类疾病恙虫病。恙虫病东方体的一个显著特征是其广泛的菌株多样性，但菌株之间的毒力差异尚未明确界定，也未得到充分了解。我们试图通过将七株菌株用于小鼠感染并结合人类流行病学数据，以相对毒力对每株菌株进行排名，从而确定致病性的细菌驱动因素。小鼠细胞因子表达数据显示，两种毒力最强的菌株，池田株和加藤株，诱导的白细胞介素-6、白细胞介素-10、干扰素-γ和单核细胞趋化蛋白-1水平高于其他菌株，这与重症恙虫病患者体内这些细胞因子水平升高一致。我们试图通过比较它们的基因组、体外生长特性以及宿主细胞中细胞因子/趋化因子的诱导情况，来确定所观察到的菌株间毒力差异的机制基础。我们发现，没有单个基因或基因组与毒力相关，也没有明确的体外生长速率模式可预测疾病。然而，基于显微镜的细胞内感染周期分析表明，我们研究中唯一完全无毒的菌株TA686，在亚细胞定位及其表面蛋白ScaC的表达方面与所有有毒菌株不同。这使我们得出一个模型，即恙虫病东方体致病性的驱动因素分布在整个基因组中，可能存在于不同菌株编码的大量且多样的效应蛋白库中，并且这些因素以复杂的方式相互作用，从而在哺乳动物宿主中诱导不同的免疫反应，进而导致不同的疾病结果。
