Orientia tsutsugamushi Infection Stimulates Syk-Dependent Responses and Innate Cytosolic Defenses in Macrophages.
Orientia tsutsugamushi Infection Stimulates Syk-Dependent Responses and Innate Cytosolic Defenses in Macrophages.
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DOI：
10.3390/pathogens12010053
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发表时间：
2022-12-29
期刊：
影响因子：
3.7
通讯作者：
Soong, Lynn
中科院分区：
文献类型：
--
作者：
Fisher, James;Gonzales, Casey;Chroust, Zachary;Liang, Yuejin;Soong, Lynn
关键词：
恙虫病东方体是一种专性细胞内细菌，是恙虫病的病原。恙虫病的人体研究和动物模型显示，在严重感染期间，有强烈的1型偏斜促炎反应。巨噬细胞（MΦ）在启动这些反应中起着关键作用，但对恙虫病虫体的先天识别机制尚不清楚。在这项研究中，我们研究了syk依赖性c型凝集素受体（CLRs）是否参与先天免疫识别和促炎反应的产生。为了验证clr在恙虫病中的作用，我们在选择性Syk抑制剂存在的情况下，用恙虫病恙虫体感染小鼠骨髓来源的MΦ，并通过qRT-PCR分析了一组clr和促炎标志物。我们发现，在感染后6小时，Syk抑制后，Mincle/Clec4a和Clec5a的转录显著减少。Western blot验证Syk对Mincle蛋白表达的影响。syk抑制MΦ在感染期间降低了1型细胞因子/趋化因子（Il12p40, Tnf, Il27p28, Cxcl1）的表达。此外，在致死性感染小鼠的大脑中，先天免疫细胞质传感器（Mx1和Oas1-3）的表达被高度诱导。我们发现，在Syk抑制的MΦ中，Mx1和Oas1的表达降低，而Oas2、Oas3和MerTK对Syk抑制不敏感。这项研究揭示了syk依赖性clr对恙虫病的炎症反应有贡献。它还提供了感染期间syk依赖性细胞内防御激活的第一个证据，表明模式识别受体串扰在协调巨噬细胞介导的对这种研究较少的细菌的反应中的作用。
Orientia tsutsugamushi is an obligately intracellular bacterium and an etiological agent of scrub typhus. Human studies and animal models of scrub typhus have shown robust type 1-skewed proinflammatory responses during severe infection. Macrophages (MΦ) play a critical role in initiating such responses, yet mechanisms of innate recognition for O. tsutsugamushi remain unclear. In this study, we investigated whether Syk-dependent C-type lectin receptors (CLRs) contribute to innate immune recognition and the generation of proinflammatory responses. To validate the role of CLRs in scrub typhus, we infected murine bone marrow-derived MΦ with O. tsutsugamushi in the presence of selective Syk inhibitors and analyzed a panel of CLRs and proinflammatory markers via qRT-PCR. We found that Mincle/Clec4a and Clec5a transcription was significantly abrogated upon Syk inhibition at 6 h of infection. The effect of Syk inhibition on Mincle protein expression was validated via Western blot. Syk-inhibited MΦ had diminished expression of type 1 cytokines/chemokines (Il12p40, Tnf, Il27p28, Cxcl1) during infection. Additionally, expression of innate immune cytosolic sensors (Mx1 and Oas1-3) was highly induced in the brain of lethally infected mice. We established that Mx1 and Oas1 expression was reduced in Syk-inhibited MΦ, while Oas2, Oas3, and MerTK were not sensitive to Syk inhibition. This study reveals that Syk-dependent CLRs contribute to inflammatory responses against O. tsutsugamushi. It also provides the first evidence for Syk-dependent activation of intracellular defenses during infection, suggesting a role of pattern recognition receptor crosstalk in orchestrating macrophage-mediated responses to this poorly studied bacterium.
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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
DOI：
10.1038/nri3719
发表时间：
2014-08
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
Hornung V;Hartmann R;Ablasser A;Hopfner KP
通讯作者：
Hopfner KP
影响因子：
2.9
作者：
Jiang J;Richards AL
通讯作者：
Richards AL
影响因子：
8.3
作者：
He Y;Xu L;Li B;Guo ZN;Hu Q;Guo Z;Tang J;Chen Y;Zhang Y;Tang J;Zhang JH
通讯作者：
Zhang JH
模式识别受体 Mincle 对于维持急性肾脏炎症中的 M1 巨噬细胞表型至关重要
影响因子：
19.6
作者：
Lv, Lin L.;Tang, Patrick Ming-Kuen;Lan, Hui-Yao
通讯作者：
Lan, Hui-Yao