Host transcriptomic profiling of CD-1 outbred mice with severe clinical outcomes following infection with Orientia tsutsugamushi.
Host transcriptomic profiling of CD-1 outbred mice with severe clinical outcomes following infection with Orientia tsutsugamushi.
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DOI：
10.1371/journal.pntd.0010459
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发表时间：
2022-11
影响因子：
3.8
通讯作者：
Soong, Lynn
中科院分区：
文献类型：
--
作者：
Thiriot, Joseph;Liang, Yuejin;Fisher, James;Walker, David H.;Soong, Lynn
恙虫病东方体是一种专性细胞内细菌，具有内皮性，可引起轻度至致命的人类恙虫病。没有疫苗可用于这种再次出现和严重被忽视的感染。先前的恙虫病研究使用了近亲繁殖的小鼠，但这种模型具有内在的局限性。因此，开发合适的小鼠模型，更好地模拟人类疾病，是免疫学研究和未来疫苗研究的迫切需要。本研究的目的是在远交系CD-1小鼠中建立恙虫病，并确定与疾病严重程度相关的免疫生物标志物。CD-1小鼠经静脉注射途径感染恙虫病卡普株；感染后2-12天采集主要器官进行动力学分析。我们发现，在给定的感染剂量下，CD-1小鼠明显比近亲繁殖的C57BL/6小鼠（0-10%致死）更易感（90-100%致死）。感染CD-1小鼠器官的大体病理显示模仿人类恙虫病的特征，包括肺水肿、间质性肺炎、血管周围淋巴细胞浸润和血管炎。炎症肺中血管生成素/受体表达的改变暗示内皮功能障碍。使用NanoString分析的肺免疫基因谱显示Th1/ cd8偏斜，但Th2抑制谱，包括以前未在其他恙虫病模型中研究的新生物标志物。Bio-plex分析显示，CD-1小鼠中存在强烈的炎症反应，血清细胞因子和趋化因子水平升高证明了这一点，这与疾病严重阶段的免疫细胞募集相关。该研究提供了一个重要的框架，表明CD-1小鼠在描述宿主对恙虫病的易感性、免疫失调和疾病发病机制方面的价值。这种临床前模型对未来严重恙虫病的转化和疫苗研究特别有用。恙虫病是一种被严重忽视的潜在致命疾病，由恙虫病东方体引起，恙虫病东方体是一种遗传上难治的细胞内特异性细菌，每年全世界至少有100万人感染。没有可用的疫苗，我们目前对宿主免疫反应和机制的了解仍然非常有限。能够概括该疾病的适当感染动物模型对于开发有效的治疗方法和疫苗至关重要。在这项研究中，我们通过转录组学和Bio-plex检测鉴定了罹患致命恙虫病的远交种CD-1小鼠的免疫应答。我们发现CD-1小鼠对感染非常敏感，并且在疾病急性期，高死亡率与Th1/ cd8偏斜但Th2抑制的免疫谱相关。血清中细胞因子和趋化因子水平的升高进一步证实了这种促炎状态。总的来说，本研究建立了CD-1小鼠作为一种实用的临床前模型，以确定严重恙虫病的致病机制，并为未来恙虫病恙虫病感染期间的免疫学和转化研究提供基础。
Orientia tsutsugamushi is an obligately intracellular bacterium with endothelial tropism and can cause mild to lethal scrub typhus in humans. No vaccine is available for this reemerging and severely neglected infection. Previous scrub typhus studies have utilized inbred mice, yet such models have intrinsic limitations. Thus, the development of suitable mouse models that better mimic human diseases is in great need for immunologic investigation and future vaccine studies. This study is aimed at establishing scrub typhus in outbred CD-1 mice and defining immune biomarkers related to disease severity. CD-1 mice received O. tsutsugamushi Karp strain via the i.v. route; major organs were harvested at 2–12 days post-infection for kinetic analyses. We found that for our given infection doses, CD-1 mice were significantly more susceptible (90–100% lethal) than were inbred C57BL/6 mice (0–10% lethal). Gross pathology of infected CD-1 mouse organs revealed features that mimicked human scrub typhus, including pulmonary edema, interstitial pneumonia, perivascular lymphocytic infiltrates, and vasculitis. Alteration in angiopoietin/receptor expression in inflamed lungs implied endothelial dysfunction. Lung immune gene profiling using NanoString analysis displayed a Th1/CD8-skewed, but Th2 repressed profile, including novel biomarkers not previously investigated in other scrub typhus models. Bio-plex analysis revealed a robust inflammatory response in CD-1 mice as evidenced by increased serum cytokine and chemokine levels, correlating with immune cell recruitment during the severe stages of the disease. This study provides an important framework indicating a value of CD-1 mice for delineating host susceptibility to O. tsutsugamushi, immune dysregulation, and disease pathogenesis. This preclinical model is particularly useful for future translational and vaccine studies for severe scrub typhus. Scrub typhus is a severely neglected and potentially fatal disease caused by Orientia tsutsugamushi, a genetically intractable, obligately intracellular bacterium that annually infects at least one million people worldwide. There is no vaccine available, and our current understanding of the host immunological response and mechanisms remains very limited. Appropriate animal models of infection that recapitulate the disease are essential to the development of effective therapeutics and vaccines. In this study, we characterized the immunologic responses by transcriptomics and Bio-plex assays in outbred CD-1 mice with lethal O. tsutsugamushi infection. We found that CD-1 mice were highly susceptible to infection and that the high mortality correlated with a Th1/CD8-skewed, but Th2 repressed, immune profile during the acute phase of disease. This proinflammatory state was further confirmed by elevated cytokine and chemokine levels in the sera. Collectively, this study established CD-1 mice as a practical, preclinical model to define pathogenic mechanisms underlying severe scrub typhus and for future immunologic and translational studies during O. tsutsugamushi infection.
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