Murine Cytomegalovirus Spreads by Dendritic Cell Recirculation.
Murine Cytomegalovirus Spreads by Dendritic Cell Recirculation.
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DOI：
10.1128/mbio.01264-17
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发表时间：
2017-10-03
期刊：
影响因子：
6.4
通讯作者：
Stevenson PG
中科院分区：
文献类型：
--
作者：
Farrell HE;Bruce K;Lawler C;Oliveira M;Cardin R;Davis-Poynter N;Stevenson PG
疱疹病毒已经与它们的宿主共同进化了数亿年，并利用了它们生物学的基本特征。巨细胞病毒（CMV）定殖于血液传播的骨髓细胞，并且已经假设全身传播是由骨髓中受感染的干细胞引起的。然而，干细胞移植的CMV转移较差，这反对成为主要的储库。为了确定巨细胞病毒传播的替代途径，我们追踪了进入粘膜后的小鼠巨细胞病毒（MCMV）定植。我们发现，鼻内MCMV感染后，肺CD11c+树突状细胞（DC）迁移顺序淋巴结（LN），血液，然后唾液腺。复制缺陷型病毒遵循相同的途径，因此，DC感染外周穿过LN进入血液。鉴于DC被认为在其到达并整合到LN中后局部死亡，再循环到血液中代表了一种新的途径。我们研究了宿主和病毒因素，促进这LN的穿越。我们发现，MCMV感染的DC退出LN淋巴细胞的一个独特的途径，进入高内皮微静脉和绕过传出淋巴。LN的退出需要CD44和病毒M33趋化因子受体，没有它们，感染的DC在LN中积累，全身扩散大大减少。综上所述，我们的研究首次证明了病毒驱动的DC再循环。由于病毒遵循宿主定义的途径，高内皮微静脉通常允许DC从LN返回血液。人巨细胞病毒（HCMV）在未出生的胎儿和免疫功能低下的人中引起毁灭性疾病。目前还没有获得许可的疫苗，我们对宿主定植的早期事件缺乏了解，阻碍了预防措施。HCMV和鼠CMV（MCMV）均感染血液传播的骨髓细胞。HCMV感染的血细胞被认为是来自受感染的骨髓干细胞。然而，受感染的干细胞在体内没有可视化，也没有显示出离体产生病毒，并且造血移植很少转移感染。我们发现，MCMV感染的树突状细胞在肺部通过淋巴结到达血液，令人惊讶地迁移到高内皮微静脉。传播不需要病毒复制。它依赖于组成型活性病毒趋化因子受体M33和宿主透明质酸受体CD 44。因此，病毒趋化因子受体是限制系统性CMV感染的可能靶点。
Herpesviruses have coevolved with their hosts over hundreds of millions of years and exploit fundamental features of their biology. Cytomegaloviruses (CMVs) colonize blood-borne myeloid cells, and it has been hypothesized that systemic dissemination arises from infected stem cells in bone marrow. However, poor CMV transfer by stem cell transplantation argues against this being the main reservoir. To identify alternative pathways for CMV spread, we tracked murine CMV (MCMV) colonization after mucosal entry. We show that following intranasal MCMV infection, lung CD11c+ dendritic cells (DC) migrated sequentially to lymph nodes (LN), blood, and then salivary glands. Replication-deficient virus followed the same route, and thus, DC infected peripherally traversed LN to enter the blood. Given that DC are thought to die locally following their arrival and integration into LN, recirculation into blood represents a new pathway. We examined host and viral factors that facilitated this LN traverse. We show that MCMV-infected DC exited LN by a distinct route to lymphocytes, entering high endothelial venules and bypassing the efferent lymph. LN exit required CD44 and the viral M33 chemokine receptor, without which infected DC accumulated in LN and systemic spread was greatly reduced. Taken together, our studies provide the first demonstration of virus-driven DC recirculation. As viruses follow host-defined pathways, high endothelial venules may normally allow DC to pass from LN back into blood. Human cytomegalovirus (HCMV) causes devastating disease in the unborn fetus and in the immunocompromised. There is no licensed vaccine, and preventive measures are impeded by our poor understanding of early events in host colonization. HCMV and murine CMV (MCMV) both infect blood-borne myeloid cells. HCMV-infected blood cells are thought to derive from infected bone marrow stem cells. However, infected stem cells have not been visualized in vivo nor shown to produce virus ex vivo, and hematopoietic transplants poorly transfer infection. We show that MCMV-infected dendritic cells in the lungs reach the blood via lymph nodes, surprisingly migrating into high endothelial venules. Dissemination did not require viral replication. It depended on the constitutively active viral chemokine receptor M33 and on the host hyaluronan receptor CD44. Thus, viral chemokine receptors are a possible target to limit systemic CMV infections.