Chemokine Receptor Ccr7 Restricts Fatal West Nile Virus Encephalitis
Chemokine Receptor Ccr7 Restricts Fatal West Nile Virus Encephalitis
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DOI：
10.1128/jvi.02409-16
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发表时间：
2017-05-01
影响因子：
5.4
通讯作者：
Lim, Jean K.
中科院分区：
文献类型：
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作者：
Bardina, Susana V.;Brown, Julia A.;Lim, Jean K.
西尼罗河病毒（WNV）是一种蚊子传播的黄病毒，可导致衰弱性脑炎。为了描述这种病理学背后的机制，我们研究了Ccr 7缺陷小鼠，这使我们有能力研究外周细胞运输事件中断的小鼠感染。Ccr 7的丢失导致在整个感染期间保持升高的立即泛白细胞增多。这种白细胞增多导致中枢神经系统（CNS）内白细胞蓄积显著增加。尽管CNS中存在过量的病毒特异性T细胞，但Ccr 7缺陷型小鼠的CNS病毒载量和死亡率显著高于野生型动物。从机制上讲，在Ccr 7缺陷小鼠中，感染的骨髓细胞向脑中的运输增加导致CNS中WNV水平增加，从而有效地促进神经炎症并降低病毒清除率。结合，我们的实验表明，在西尼罗河病毒感染，CCR 7是一个看门人非特异性病毒transfer到brain.IMPORTANCE在这项研究中，我们表明，CCR 7是需要足够的树突状细胞和T细胞迁移到引流淋巴结感染后立即和白细胞迁移到大脑的限制。此外，引流淋巴结中树突状细胞的严重损失对该器官中的病毒复制没有影响，表明WNV可能通过另一种机制从皮肤迁移到淋巴结中。最重要的是，我们发现Ccr 7的缺失导致显著的白细胞增多，导致CNS内的细胞过多，其中单核细胞/巨噬细胞导致CNS病毒血症、神经炎症和死亡率增加。总之，我们的数据表明Ccr 7是急性病毒感染期间限制神经炎症的关键宿主防御限制因子。
West Nile virus (WNV) is a mosquito-transmitted flavivirus that can cause debilitating encephalitis. To delineate the mechanisms behind this pathology, we studied Ccr7-deficient mice, which afforded us the capacity to study infection in mice with disrupted peripheral cellular trafficking events. The loss of Ccr7 resulted in an immediate pan-leukocytosis that remained elevated throughout the infection. This leukocytosis resulted in a significant enhancement of leukocyte accumulation within the central nervous system (CNS). Despite an excess of virus-specific T cells in the CNS, Ccr7-deficient mice had significantly higher CNS viral loads and mortality rates than wild-type animals. Mechanistically, the elevated trafficking of infected myeloid cells into the brain in Ccr7-deficient mice resulted in increased levels of WNV in the CNS, thereby effectively contributing to neuroinflammation and lowering viral clearance. Combined, our experiments suggest that during WNV infection, Ccr7 is a gatekeeper for nonspecific viral transference to the brain.IMPORTANCE In this study, we show that Ccr7 is required for the sufficient migration of dendritic cells and T cells into the draining lymph node immediately following infection and for the restriction of leukocyte migration into the brain. Further, the severe loss of dendritic cells in the draining lymph node had no impact on viral replication in this organ, suggesting that WNV may migrate from the skin into the lymph node through another mechanism. Most importantly, we found that the loss of Ccr7 results in a significant leukocytosis, leading to hypercellularity within the CNS, where monocytes/macrophages contribute to CNS viremia, neuroinflammation, and increased mortality. Together, our data point to Ccr7 as a critical host defense restriction factor limiting neuroinflammation during acute viral infection.