Interferon receptor-deficient mice are susceptible to eschar-associated rickettsiosis.
Interferon receptor-deficient mice are susceptible to eschar-associated rickettsiosis.
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DOI：
10.7554/elife.67029
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发表时间：
2021-08-23
期刊：
影响因子：
7.7
通讯作者：
Welch MD
中科院分区：
文献类型：
--
作者：
Burke TP;Engström P;Tran CJ;Langohr IM;Glasner DR;Espinosa DA;Harris E;Welch MD
节肢动物传播的立克次体病原体在世界范围内引起轻度和严重的人类疾病。蜱传病原体帕克氏立克次体在人类中引起皮肤病变（焦痂）和播散性疾病;然而，近交系小鼠通常对感染有抵抗力。我们报告，皮内感染的小鼠缺乏两个干扰素受体（Ifnar 1-/-; Ifngr 1-/-）与少至10个R。Parkeri elevenescar焦痂的形成和传播，致命的疾病。与人类感染相似，焦痂表现出坏死和炎症，细菌主要存在于白细胞中。使用这个模型，我们发现，肌动蛋白为基础的运动因子Sca 2是所需的传播从皮肤到内部器官，和外膜蛋白OmpB有助于焦痂的形成。用sca 2和ompB突变体R. parkeri保护免受再攻击，揭示了减毒活疫苗候选物。因此，Ifnar 1-/-; Ifngr 1-/-小鼠是研究立克次体病、毒力因子和免疫的易处理模型。我们的研究结果进一步表明，小鼠和人类易感性之间的差异可能是由于干扰素信号的差异。蜱虫叮咬可以让致病微生物，包括多种立克次氏体细菌，从节肢动物传给人类。例如，接触帕克氏立克次体会导致咬伤部位结痂、发烧、头痛和疲劳。到目前为止，还没有疫苗可以预防立克次体引起的任何严重疾病。在动物中模拟人类感染可能有助于理解和对抗这些疾病。R. parkeri是此类研究的良好候选者，因为它可以深入了解更严重的立克次体感染，同时处理起来相对更安全。然而，实验室小鼠对这种细菌具有抗性，限制了它们作为模型的使用。为了探索为什么会这样，Burke等人研究了一种称为干扰素信号传导的免疫机制是否能保护实验室啮齿动物免受R。parkeri。在感染过程中，免疫系统释放出一种叫做干扰素的分子，这种分子粘附在细胞表面的“受体”上，触发防御机制，帮助击退入侵者。Burke等将R. parkeri的方法注射到有或没有某种干扰素受体的小鼠皮肤上，结果表明，没有两种特定受体的动物会结痂，并看到疾病在体内传播。进一步的研究表明，两个R. parkeri蛋白，被称为OmpB或Sca 2，是细菌引起皮肤病变和损害内脏的必需品。Burke等人随后使用R.缺乏OmpB或Sca 2的parkeri，以测试这些经过修饰的无害微生物是否可以作为“疫苗”。事实上，脆弱的实验室小鼠首先接触到突变细菌，然后能够在“正常”版本的微生物中生存下来。总之，这项工作揭示了干扰素信号可以保护实验室小鼠免受R。帕克氏感染。它还创建了一个动物模型，可用于研究疾病和疫苗接种。
Arthropod-borne rickettsial pathogens cause mild and severe human disease worldwide. The tick-borne pathogen Rickettsia parkeri elicits skin lesions (eschars) and disseminated disease in humans; however, inbred mice are generally resistant to infection. We report that intradermal infection of mice lacking both interferon receptors (Ifnar1-/-;Ifngr1-/-) with as few as 10 R. parkeri elicits eschar formation and disseminated, lethal disease. Similar to human infection, eschars exhibited necrosis and inflammation, with bacteria primarily found in leukocytes. Using this model, we find that the actin-based motility factor Sca2 is required for dissemination from the skin to internal organs, and the outer membrane protein OmpB contributes to eschar formation. Immunizing Ifnar1-/-;Ifngr1-/- mice with sca2 and ompB mutant R. parkeri protects against rechallenge, revealing live-attenuated vaccine candidates. Thus, Ifnar1-/-;Ifngr1-/- mice are a tractable model to investigate rickettsiosis, virulence factors, and immunity. Our results further suggest that discrepancies between mouse and human susceptibility may be due to differences in interferon signaling. Tick bites allow disease-causing microbes, including multiple species of Rickettsia bacteria, to pass from arthropods to humans. Being exposed to Rickettsia parkeri, for example, can cause a scab at the bite site, fever, headache and fatigue. To date, no vaccine is available against any of the severe diseases caused by Rickettsia species. Modelling human infections in animals could help to understand and combat these illnesses. R. parkeri is a good candidate for such studies, as it can give insight into more severe Rickettsia infections while being comparatively safer to handle. However, laboratory mice are resistant to this species of bacteria, limiting their use as models. To explore why this is the case, Burke et al. probed whether an immune mechanism known as interferon signalling protects laboratory rodents against R. parkeri. During infection, the immune system releases molecules called interferons that stick to ‘receptors’ at the surface of cells, triggering defense mechanisms that help to fight off an invader. Burke et al. injected R. parkeri into the skin of mice that had or lacked certain interferon receptors, showing that animals without two specific receptors developed scabs and saw the disease spread through their body. Further investigation showed that two R. parkeri proteins, known as OmpB or Sca2, were essential for the bacteria to cause skin lesions and damage internal organs. Burke et al. then used R. parkeri that lacked OmpB or Sca2 to test whether these modified, inoffensive microbes could act as ‘vaccines’. And indeed, vulnerable laboratory mice which were first exposed to the mutant bacteria were then able to survive the ‘normal’ version of the microbe. Together, this work reveals that interferon signalling protects laboratory mice against R. parkeri infections. It also creates an animal model that can be used to study disease and vaccination.