TLR2 and Nod2 mediate resistance or susceptibility to fatal intracellular Ehrlichia infection in murine models of ehrlichiosis.
TLR2 and Nod2 mediate resistance or susceptibility to fatal intracellular Ehrlichia infection in murine models of ehrlichiosis.
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DOI：
10.1371/journal.pone.0058514
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Ismail N
中科院分区：
文献类型：
--
作者：
Chattoraj P;Yang Q;Khandai A;Al-Hendy O;Ismail N
我们的人单核细胞埃里希体病（HME）的鼠模型已经表明，严重和致命的埃里希体病是由于产生致病性T细胞应答导致免疫病理学和多器官衰竭。然而，肝脏（感染的主要部位）的早期事件尚不清楚。在这项研究中，我们研究了肝脏转录组的过程中，致死性和非致死性感染引起的卵形硬蜱埃里希体和鼠埃里希体，分别。在感染后（p.i.）第3天，尽管与未感染小鼠相比，两组感染小鼠中大多数宿主基因下调，但与非致死性感染相比，致死性感染诱导了caspase 1、caspase 4、含核苷酸结合寡聚化结构域蛋白（Nod 1）、肿瘤坏死因子-α、白细胞介素10和CCL 7的显著更高表达。在感染后第7天，致死性感染诱导1型干扰素、几种炎性细胞因子和趋化因子的高度显著上调，这与Toll样受体2（TLR 2）、Nod 2、MyD 88、核因子-κ B（NF-κ B）、半胱天冬酶4、NLRP 1、NLRP 12、Pycard和IL-1β的表达水平增加相关，表明TLR信号和炎性体活化增强。接下来，我们评估了TLR 2和Nod 2在致死埃里希体感染期间参与宿主应答。尽管缺乏TLR 2会损害细菌清除并增加组织坏死，但Nod 2缺陷会减轻病理并增强细菌清除，这与干扰素-γ和白细胞介素-10水平升高以及响应致死性感染的致病性CD 8 + T细胞频率降低相关。因此，这些数据表明，Nod 2，而不是TLR 2，有助于对严重埃里希体诱导的休克的易感性。总之，我们的研究首次提供了对可能导致严重HME的宿主因素和新型分子致病机制的多样性的深入了解。
Our murine models of human monocytic ehrlichiosis (HME) have shown that severe and fatal ehrlichiosis is due to generation of pathogenic T cell responses causing immunopathology and multi-organ failure. However, the early events in the liver, the main site of infection, are not well understood. In this study, we examined the liver transcriptome during the course of lethal and nonlethal infections caused by Ixodes ovatus Ehrlichia and Ehrlichia muris, respectively. On day 3 post-infection (p.i.), although most host genes were down regulated in the two groups of infected mice compared to naïve counterparts, lethal infection induced significantly higher expression of caspase 1, caspase 4, nucleotide binding oligomerization domain-containing proteins (Nod1), tumor necrosis factor-alpha, interleukin 10, and CCL7 compared to nonlethal infection. On day 7 p.i., lethal infection induced highly significant upregulation of type-1 interferon, several inflammatory cytokines and chemokines, which was associated with increased expression levels of Toll-like receptor-2 (TLR2), Nod2, MyD88, nuclear factor-kappa B (NF-kB), Caspase 4, NLRP1, NLRP12, Pycard, and IL-1β, suggesting enhanced TLR signals and inflammasomes activation. We next evaluated the participation of TLR2 and Nod2 in the host response during lethal Ehrlichia infection. Although lack of TLR2 impaired bacterial elimination and increased tissue necrosis, Nod2 deficiency attenuated pathology and enhanced bacterial clearance, which correlated with increased interferon-γ and interleukin-10 levels and a decreased frequency of pathogenic CD8+ T cells in response to lethal infection. Thus, these data indicate that Nod2, but not TLR2, contributes to susceptibility to severe Ehrlichia-induced shock. Together, our studies provide, for the first time, insight into the diversity of host factors and novel molecular pathogenic mechanisms that may contribute to severe HME.
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