Viral and Rickettsial Diseases Department, Naval Medical Research Center, Silver Spring, Maryland, United States of America.
PLoS One. 2013;8(1):e54570. doi: 10.1371/journal.pone.0054570. Epub 2013 Jan 16.
Scrub typhus is an important endemic disease of the Asia-Pacific region caused by Orientia tsutsugamushi. To develop an effective vaccine to prevent scrub typhus infection, a better understanding of the initial host-pathogen interaction is needed. The objective of this study was to investigate early bacterial dissemination in a CD-1 Swiss outbred mouse model after intradermal injection of O. tsutsugamushi. Three human pathogenic strains of O. tsutsugamushi (Karp, Gilliam, and Woods) were chosen to investigate the early infection characteristics associated with bacterial virulence. Tissue biopsies of the intradermal injection site and draining lymph nodes were examined using histology and immunohistochemistry to characterize bacterial dissemination, and correlated with quantitative real-time PCR for O. tsutsugamushi in blood and tissue from major organs. Soluble adhesion molecules were measured to examine cellular activation in response to infection. No eschar formation was seen at the inoculation site and no clinical disease developed within the 7 day period of observation. However, O. tsutsugamushi was localized at the injection site and in the draining lymph nodes by day 7 post inoculation. Evidence of leukocyte and endothelial activation was present by day 7 with significantly raised levels of sL-selectin, sICAM-1 and sVCAM-1. Infection with the Karp strain was associated with earlier and higher bacterial loads and more extensive dissemination in various tissues than the less pathogenic Gilliam and Woods strains. The bacterial loads of O. tsutsugamushi were highest in the lungs and spleens of mice inoculated with Karp and Gilliam, but not Woods strains. Strains of higher virulence resulted in more rapid systemic infection and dissemination in this model. The CD-1 mouse intradermal inoculation model demonstrates features relevant to early scrub typhus infection in humans, including the development of regional lymphadenopathy, leukocyte activation and distant organ dissemination after low-dose intradermal injection with O. tsutsugamushi.
恙虫病是亚太地区一种重要的地方性疾病，由恙虫病东方体引起。为了开发预防恙虫病感染的有效疫苗，需要更好地了解初始宿主-病原体相互作用。本研究的目的是研究 CD-1 瑞士杂交小鼠模型中经皮注射恙虫病东方体后早期细菌播散情况。选择了三种人类致病性恙虫病东方体（Karp、Gilliam 和 Woods）菌株，以研究与细菌毒力相关的早期感染特征。使用组织学和免疫组织化学检查皮内注射部位和引流淋巴结的组织活检，以描述细菌播散，并与血液和主要器官组织中的恙虫病东方体定量实时 PCR 相关联。测量可溶性粘附分子以检查感染后细胞的激活情况。接种部位未见焦痂形成，观察期 7 天内未发生临床疾病。然而，接种后第 7 天，在接种部位和引流淋巴结中定位到恙虫病东方体。第 7 天存在白细胞和内皮细胞激活的证据，sL-选择素、sICAM-1 和 sVCAM-1 的水平显著升高。与致病性较低的 Gilliam 和 Woods 菌株相比，Karp 菌株的感染与更早和更高的细菌负荷以及更广泛的组织播散有关。接种 Karp 和 Gilliam 菌株的小鼠肺部和脾脏中的恙虫病东方体细菌负荷最高，但 Woods 菌株则不然。毒力更高的菌株导致该模型中更快速的全身感染和播散。CD-1 小鼠皮内接种模型显示出与人类早期恙虫病感染相关的特征，包括局部淋巴结病、白细胞激活和经皮低剂量注射恙虫病东方体后远处器官播散的发展。
