A time-course comparative clinical and immune response evaluation study between the human pathogenic Orientia tsutsugamushi strains: Karp and Gilliam in a rhesus macaque (Macaca mulatta) model.
A time-course comparative clinical and immune response evaluation study between the human pathogenic Orientia tsutsugamushi strains: Karp and Gilliam in a rhesus macaque (Macaca mulatta) model.
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DOI：
10.1371/journal.pntd.0010611
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发表时间：
2022-08
影响因子：
3.8
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中科院分区：
文献类型：
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恙虫病是一种由恙虫病东方体通过恙螨叮咬传播的媒介传播的发热性疾病。O.恙虫病具有高度的遗传多样性，人们越来越认识到它在全球的分布比以前所认为的要广泛。我们评估了两种最相关的人类致病O。恙虫病; Karp（n = 4）和Gilliam（n = 4）在标准化恙虫病非人灵长类恒河猴模型中进行的感染后（dpi）80天的时程研究。我们观察到两种菌株之间的临床进展和免疫反应的不同特征;与Karp菌株相比，Gilpendin感染的猕猴发生了更明显的全身感染，其特征是感染急性期的菌血症、淋巴结肿大、焦痂病变和更高的炎症标志物。C-反应蛋白（CRP）血浆水平、干扰素γ（IFN-γ）、白细胞介素-1受体拮抗剂（IL-1 ra）、IL-15血清浓度、CRP/IL-10和IFN-γ/IL-10比值与血液中的细菌载量呈正相关，这意味着先天免疫应答的激活和T辅助细胞1型免疫应答的优先发展。手术与Karp感染组相比，在80 dpi时从皮肤和淋巴结中分离的细胞中的恙虫病特异性免疫记忆应答在Gilpidae感染的猕猴中更显著地升高。比较两种菌株的细胞因子应答动力学，发现IFN-γ、肿瘤坏死因子（TNF）、IL-15、IL-6、IL-18、调节性IL-1 ra、IL-10、IL-8和粒细胞集落刺激因子（G-CSF）显著上调。这些数据表明，临床结果和宿主对恙虫病的免疫反应可能与促炎和抗炎的精氨酸介导的反应的平衡作用有关。目前，没有数据的特征时间过程比较O。关于疾病严重性和免疫应答的测量的恙虫病菌株是可用的。我们的研究为恙虫病宿主反应的菌株特异性提供了证据，这支持了我们对初始接种部位（焦痂）过程、全身性疾病进展、保护性和/或致病性宿主免疫机制以及细胞免疫记忆功能的理解。本研究描述了一种用于恙虫病的改进的恒河猴皮内激发模型，其中Gilliam菌株感染与恒河猴模型中比先前Karp菌株感染更高的疾病严重程度相关。通过在远交系小鼠中使用功能性接种物滴定，克服了与专性细胞内细菌的接种物定量相关的困难。基于Gilbert的恒河猴模型提供了改进的终点测量，并有助于识别未来疫苗开发的保护相关性。恙虫病是一种螨传播的立克次体疾病，如果不治疗或诊断延误或错过，可能会很严重。这种容易治疗的疾病在亚洲东南部和东部地区流行，但越来越多地被认为具有全球分布。在地方病流行地区，受感染的媒介传播恙虫病东方体的不同菌株-恙虫病的病原体-这些细菌菌株的多样性对开发有效的诊断和通用的恙虫病疫苗构成了严重障碍。针对不同菌株的宿主免疫应答的比较研究很少，并且在疾病过程中菌株特异性免疫应答的证据有限。在这项研究中，我们在一个已充分表征的非人灵长类恒河猴模型中描述了从感染开始到完全康复的临床疾病进展，该模型感染了两种最流行的O.恙虫病菌株; Karp和Gillam，并比较了菌血症的时程动力学与各种免疫应答机制的相关性。我们发现，Gilliam菌株感染与较高的疾病严重程度，较早发生菌血症，淋巴结肿大，焦痂病变和较高的炎症标志物在感染的急性期，当与卡普菌株。研究结果表明，与Karp菌株感染相比，恒河猴中的Gilliam菌株感染提供了改进的终点测量，这对未来的疫苗开发很有用。
Scrub typhus is a vector-borne febrile illness caused by Orientia tsutsugamushi transmitted by the bite of Trombiculid mites. O. tsutsugamushi has a high genetic diversity and is increasingly recognized to have a wider global distribution than previously assumed. We evaluated the clinical outcomes and host immune responses of the two most relevant human pathogenic strains of O. tsutsugamushi; Karp (n = 4) and Gilliam (n = 4) in a time-course study over 80 days post infection (dpi) in a standardized scrub typhus non-human primate rhesus macaque model. We observed distinct features in clinical progression and immune response between the two strains; Gilliam-infected macaques developed more pronounced systemic infection characterized by an earlier onset of bacteremia, lymph node enlargement, eschar lesions and higher inflammatory markers during the acute phase of infection, when compared to the Karp strain. C-reactive protein (CRP) plasma levels, interferon gamma (IFN-γ, interleukin-1 receptor antagonist (IL-1ra), IL-15 serum concentrations, CRP/IL10- and IFN-γ/IL-10 ratios correlated positively with bacterial load in blood, implying activation of the innate immune response and preferential development of a T helper-type 1 immune response. The O. tsutsugamushi-specific immune memory responses in cells isolated from skin and lymph nodes at 80 dpi were more markedly elevated in the Gilliam-infected macaques than in the Karp-infected group. The comparative cytokine response dynamics of both strains revealed significant up-regulation of IFN-γ, tumor necrosis factor (TNF), IL-15, IL-6, IL-18, regulatory IL-1ra, IL-10, IL-8 and granulocyte-colony-stimulating factor (G-CSF). These data suggest that the clinical outcomes and host immune responses to scrub typhus could be associated with counter balancing effects of pro- and anti-inflammatory cytokine-mediated responses. Currently, no data on characterized time-course comparisons of O. tsutsugamushi strains regarding measures of disease severity and immune response is available. Our study provides evidence for the strain-specificity of host responses in scrub typhus, which supports our understanding of processes at the initial inoculation site (eschar), systemic disease progression, protective and/or pathogenic host immune mechanisms and cellular immune memory function. This study characterised an improved intradermal rhesus macaque challenge model for scrub typhus, whereby the Gilliam strain infection associated with higher disease severity in the rhesus macaque model than the previous Karp strain infection. Difficulties associated with inoculum quantitation for obligate-intracellular bacteria were overcome by using functional inoculum titrations in outbred mice. The Gilliam-based rhesus macaque model provides improved endpoint measurements and contributes towards the identification of correlates of protection for future vaccine development. Scrub typhus is a mite-borne rickettsial illness, which is potentially severe if untreated or diagnosis is delayed or missed. This easily treatable disease is endemic in southeastern and eastern parts of Asia, but is increasingly recognised to have a global distribution. In endemic areas, where infected vectors transmit different strains of Orientia tsutsugamushi—the causative pathogen of scrub typhus—the diversity of these bacterial strains poses a serious obstacle for developing effective diagnostics and a universal scrub typhus vaccine. Comparison studies on the host immune responses against various strains are rare and there is limited evidence on strain-specific immune responses over the disease course. In this study, we characterized the clinical disease progression from the start of infection to full convalescence in a well-characterised non-human primate rhesus macaque model, infected with the two most prevalent O. tsutsugamushi strains; Karp and Gillam, and compared the time course dynamics of bacteremia with correlations of various immune response mechanisms. We found that Gilliam strain infection associated with higher disease severity, earlier onset of bacteremia, lymph node enlargement, eschar lesions and higher inflammatory markers during the acute phase of infection, when compared to the Karp strain. The findings suggest that a Gilliam strain infection in rhesus macaques provides improved endpoint measurements when compared to Karp strain infections, which is useful for future vaccine development.
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