Orientia tsutsugamushi selectively stimulates the C-type lectin receptor Mincle and type 1-skewed proinflammatory immune responses.
Orientia tsutsugamushi selectively stimulates the C-type lectin receptor Mincle and type 1-skewed proinflammatory immune responses.
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DOI：
10.1371/journal.ppat.1009782
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发表时间：
2021-07
期刊：
影响因子：
6.7
通讯作者：
Soong L
中科院分区：
文献类型：
--
作者：
Fisher J;Card G;Liang Y;Trent B;Rosenzweig H;Soong L
恙虫病东方体是一种专性细胞内细菌，也是恙虫病的病原体。肺部是感染的主要靶器官，表现出 1 型偏向的促炎反应。肺损伤和急性呼吸窘迫综合征是严重恙虫病的常见并发症；然而，其潜在机制仍不清楚。在这项研究中，我们研究了 C 型凝集素受体 (CLR) Mincle 是否有助于免疫识别和失调。小鼠致死感染后，我们使用 NanoString 进行了肺部差异表达分析。在检查的 671 个基因中，我们发现 312 个基因在疾病末期显着表达。 Mincle (Clec4e) 是上调最多的 5 个基因之一，与其信号伙伴、1 型偏态趋化因子（Cxcr3、Ccr5 及其配体）以及 Il27 一起。为了验证 Mincle 在恙虫病中的作用，我们将小鼠骨髓来源的巨噬细胞 (MΦ) 暴露于活的或灭活的恙虫病锥体，并通过 qRT-PCR 分析了一组 CLR 和促炎标记物。我们发现，虽然热灭活的细菌刺激了短暂的 Mincle 表达，但活细菌在 MΦ 中产生了强烈的反应，这一点通过间接免疫荧光和蛋白质印迹得到了验证。值得注意的是，感染对其他测试的 CLR 或 TLR 的影响有限。 MΦ 中持续的促炎基因表达（Cxcl9、Ccl2、Ccl5、Nos2、Il27）是由活细菌而非灭活细菌诱导的；与 WT 细胞相比，感染的 Mincle-/- MΦ 显着降低了促炎反应。总之，这项研究为 Mincle 在感知恙虫病中的选择性表达提供了第一个证据，并表明 Mincle 和 IL-27 相关途径在宿主对严重感染的反应中具有潜在作用。此外，它还为这种研究不足的细菌的先天免疫识别提供了新的见解。恙虫病是一种由恙虫病东方体细菌引起的危及生命的疾病。严重疾病通常涉及肺部，弥漫性肺泡损伤可导致显着的发病率和死亡率。人们认为免疫反应失调会导致严重疾病的发生；然而，免疫系统如何感知恙虫病并对其做出反应仍不清楚。在这项研究中，我们使用了恙虫病致死小鼠模型以及培养的巨噬细胞和中性粒细胞，来检查感染过程中可能涉及的免疫传感器和炎症反应。我们发现恙虫病可选择性刺激受感染小鼠肺部的 C 型凝集素受体 Mincle，同时促炎和 1 型反应标记物增加。我们还发现，用活细菌或灭活细菌处理的巨噬细胞增加了 Mincle 表达以及 1 型和 M1 促炎标记物，其中一些在 Mincle-/- 细胞中显着减少。活的和灭活的恙虫病蜱虫激活 Mincle 及其相关炎症可能会产生过度的免疫反应，从而导致急性组织损伤。这项研究为恙虫病免疫识别提供了新的见解，并为评估恙虫病免疫失调提供了新的框架。
Orientia tsutsugamushi is an obligately intracellular bacterium and the etiological agent of scrub typhus. The lung is a major target organ of infection, displaying type 1-skewed proinflammatory responses. Lung injury and acute respiratory distress syndrome are common complications of severe scrub typhus; yet, their underlying mechanisms remain unclear. In this study, we investigated whether the C-type lectin receptor (CLR) Mincle contributes to immune recognition and dysregulation. Following lethal infection in mice, we performed pulmonary differential expression analysis with NanoString. Of 671 genes examined, we found 312 significantly expressed genes at the terminal phase of disease. Mincle (Clec4e) was among the top 5 greatest up-regulated genes, accompanied with its signaling partners, type 1-skewing chemokines (Cxcr3, Ccr5, and their ligands), as well as Il27. To validate the role of Mincle in scrub typhus, we exposed murine bone marrow-derived macrophages (MΦ) to live or inactivated O. tsutsugamushi and analyzed a panel of CLRs and proinflammatory markers via qRT-PCR. We found that while heat-killed bacteria stimulated transitory Mincle expression, live bacteria generated a robust response in MΦ, which was validated by indirect immunofluorescence and western blot. Notably, infection had limited impact on other tested CLRs or TLRs. Sustained proinflammatory gene expression in MΦ (Cxcl9, Ccl2, Ccl5, Nos2, Il27) was induced by live, but not inactivated, bacteria; infected Mincle-/- MΦ significantly reduced proinflammatory responses compared with WT cells. Together, this study provides the first evidence for a selective expression of Mincle in sensing O. tsutsugamushi and suggests a potential role of Mincle- and IL-27-related pathways in host responses to severe infection. Additionally, it provides novel insight into innate immune recognition of this poorly studied bacterium. Scrub typhus is a life-threatening disease caused by the bacterium Orientia tsutsugamushi. Severe disease often involves the lung, where diffuse alveolar damage can lead to significant morbidity and mortality. It is thought that dysregulated immune responses contribute to the development of severe disease; however, it remains unknown as to how the immune system senses and responds to O. tsutsugamushi. In this study, we used a lethal mouse model of scrub typhus, along with cultured macrophages and neutrophils, to examine immune sensors and inflammatory responses which may be involved during infection. We found that O. tsutsugamushi selectively stimulated the C-type lectin receptor Mincle in the lungs of infected mice, which was accompanied by increased markers of proinflammatory and type 1-responses. We also found that macrophages treated with live or inactivated bacteria increased Mincle expression alongside type 1 and M1 proinflammatory markers, some of which were markedly decreased in Mincle-/- cells. Activation of Mincle and its associated inflammatory profile by both live and inactivated O. tsutsugamushi may generate an overzealous immune response that contributes to acute tissue damage. This study provides novel insight into immune recognition of O. tsutsugamushi and a new framework for evaluating immune dysregulation in scrub typhus.
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DOI：
10.1038/nri2569
发表时间：
2009-07
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
Geijtenbeek TB;Gringhuis SI
通讯作者：
Gringhuis SI
影响因子：
2.9
作者：
Jiang J;Richards AL
通讯作者：
Richards AL
影响因子：
3.8
作者：
Giengkam, Suparat;Blakes, Alex;Salje, Jeanne
通讯作者：
Salje, Jeanne
影响因子：
16.6
作者：
Lee WB;Kang JS;Choi WY;Zhang Q;Kim CH;Choi UY;Kim-Ha J;Kim YJ
通讯作者：
Kim YJ
髓样C型凝集素受体自我和非自身感测后的信号传导多功能性。
影响因子：
2.8
作者：
Iborra, Salvador;Sancho, David
通讯作者：
Sancho, David