Differential cellular immune responses against Orientia tsutsugamushi Karp and Gilliam strains following acute infection in mice.
Differential cellular immune responses against Orientia tsutsugamushi Karp and Gilliam strains following acute infection in mice.
复制标题
DOI：
10.1371/journal.pntd.0011445
复制
发表时间：
2023-12
影响因子：
3.8
通讯作者：
中科院分区：
文献类型：
--
作者：
恙虫病是流行国家发热性疾病的主要原因，原因是感染恙虫病东方体（一种严重缺乏研究的细胞内细菌）。与血管寄生相关的肺部病变在患者中很常见，并可发展为危及生命的间质性肺炎。Ot基因型的不同抗原性和菌株间基因组含量的差异与不同的毒力和临床结果有关；然而，在人类患者或小动物感染模型中，缺乏菌株相关肺免疫反应的详细研究。在这项研究中，我们使用了两种临床流行的细菌菌株（Karp和Gilliam）来揭示发炎肺部的细胞免疫反应和疾病严重程度的潜在生物标志物。结果表明，近交CD-1小鼠对Karp和Gilliam菌株均高度敏感；而C57BL/6 （B6）小鼠对Karp易感，对Gilliam耐药（具有自限性感染），这与C57BL/6小鼠的组织细菌负荷和肺部病理改变相对应。对灌注的B6小鼠肺的多色流式细胞术分析显示，在Karp感染期间，先天免疫细胞（巨噬细胞、中性粒细胞和NK细胞）、CD4+和CD8+ T细胞强劲持续地内流和激活，但在Gilliam感染期间，这种反应大大减弱。karp感染的B6小鼠的细胞反应与早期和高水平的血清细胞因子/趋化因子蛋白水平（CXCL1、CCL2/3/5和G-CSF）以及肺基因表达（CXCL1 /2、Ccl2/3/4和Ifng）呈正相关。体外感染B6小鼠源性原代巨噬细胞也揭示了菌株依赖的免疫基因表达谱。本研究为Karp和Gilliam感染的差异组织细胞反应提供了证据线，为未来研究Ot菌株相关的疾病发病机制和感染控制机制提供了框架。恙虫病东方体感染引起的恙虫病是流行国家发热性疾病的主要原因。对组织和血液样本中与Ot菌株相关的疾病结果或免疫特征的研究非常有限。使用两种临床流行的菌株（Karp和Gilliam），我们在近交和远交小鼠模型中检测了宿主的易感性。这些感染小动物模型的应用为急性感染阶段肺免疫细胞亚群的激活提供了新的证据。gilliam感染的C57BL/6 （B6）小鼠出现了自限性感染、轻微的细胞反应和组织损伤，而Karp感染导致先天免疫细胞的强烈和持续激活，随后是激活T细胞的大量涌入，这与血清样本中炎症细胞因子/趋化因子水平的增加有关。我们还提供了Ot菌株依赖免疫基因谱的体外证据，表明巨噬细胞对Karp和Gilliam细菌的不同反应。这是对不同恙虫病小鼠模型的首次比较，并深入分析了炎症肺部的细胞反应，为Ot菌株相关的疾病进展与感染控制的潜在机制提供了新的见解，并为未来的研究奠定了基础。
Scrub typhus is a leading cause of febrile illness in endemic countries due to infection with Orientia tsutsugamushi (Ot), a seriously understudied intracellular bacterium. Pulmonary involvement associated with vascular parasitism in patients is common and can develop into life threatening interstitial pneumonia. The diverse antigenicity of Ot genotypes and inter-strain differences in genome content are connected to varied virulence and clinical outcomes; however, detailed studies of strain-related pulmonary immune responses in human patients or small animal models of infection are lacking. In this study, we have used two clinically prevalent bacterial strains (Karp and Gilliam) to reveal cellular immune responses in inflamed lungs and potential biomarkers of disease severity. The results demonstrate that outbred CD-1 mice are highly susceptible to both Karp and Gilliam strains; however, C57BL/6 (B6) mice were susceptible to Karp, but resistant to Gilliam (with self-limiting infection), corresponding to their tissue bacterial burdens and lung pathological changes. Multicolor flow cytometric analyses of perfused B6 mouse lungs revealed robust and sustained influx and activation of innate immune cells (macrophages, neutrophils, and NK cells), followed by CD4+ and CD8+ T cells, during Karp infection, but such responses were greatly attenuated during Gilliam infection. The robust cellular responses in Karp-infected B6 mice positively correlated with significantly early and high levels of serum cytokine/chemokine protein levels (CXCL1, CCL2/3/5, and G-CSF), as well as pulmonary gene expression (Cxcl1/2, Ccl2/3/4, and Ifng). In vitro infection of B6 mouse-derived primary macrophages also revealed bacterial strain-dependent immune gene expression profiles. This study provided the lines of evidence that highlighted differential tissue cellular responses against Karp vs. Gilliam infection, offering a framework for future investigation of Ot strain-related mechanisms of disease pathogenesis vs. infection control. Orientia tsutsugamushi (Ot) infection-induced scrub typhus is a leading cause of febrile illness in endemic countries. Research on Ot strain-related disease outcomes or immune signatures in tissue and blood samples is very limited. Using two clinically prevalent strains (Karp and Gilliam), we examined host susceptibility in inbred and outbred mouse models. Application of these small animal models of infection provided new evidence for the activation of pulmonary immune cell subsets during the acute stages of infection. While Gilliam-infected C57BL/6 (B6) mice developed self-limiting infection, mild cellular responses, and tissue injury, Karp infection led to a strong and sustained activation of innate immune cells, followed by extensive influx of activated T cells, which correlated to increased levels of inflammatory cytokines/chemokines in serum samples. We also provided in vitro evidence for Ot strain-dependent immune gene profiles, indicating differential macrophage responses to Karp versus Gilliam bacteria. This is the first comparison of different scrub typhus mouse models with in-depth analyses of cellular responses in inflamed lungs, offering novel insights into potential mechanisms of disease progression versus infection control related to Ot strains and laying the foundation for future investigations.
登录
查看更多内容
影响因子：
3.7
作者：
Jablonski KA;Amici SA;Webb LM;Ruiz-Rosado Jde D;Popovich PG;Partida-Sanchez S;Guerau-de-Arellano M
通讯作者：
Guerau-de-Arellano M
影响因子：
3.8
作者：
Fisher J;Card G;Soong L
通讯作者：
Soong L
影响因子：
3.8
作者：
通讯作者：
--
影响因子：
24.1
作者：
Liang, Yuejin;Yi, Panpan;Sun, Jiaren
通讯作者：
Sun, Jiaren
影响因子：
3.7
作者：
Fisher, James;Gonzales, Casey;Chroust, Zachary;Liang, Yuejin;Soong, Lynn
通讯作者：
Soong, Lynn