Hematopoietic cell-mediated dissemination of murine cytomegalovirus is regulated by NK cells and immune evasion.
Hematopoietic cell-mediated dissemination of murine cytomegalovirus is regulated by NK cells and immune evasion.
复制标题
DOI：
10.1371/journal.ppat.1009255
复制
发表时间：
2021-01
期刊：
影响因子：
6.7
通讯作者：
Snyder CM
中科院分区：
文献类型：
--
作者：
Zhang S;Springer LE;Rao HZ;Espinosa Trethewy RG;Bishop LM;Hancock MH;Grey F;Snyder CM
巨细胞病毒（CMV）在免疫受损和免疫不成熟的个体中引起临床上重要的疾病。主要基于在鼠（M）CMV的小鼠模型中的工作，有一种共识，即骨髓细胞对于从感染部位传播CMV是重要的。理论上，这种传播应使CMV暴露于细胞介导的免疫，因此需要逃避T细胞和NK细胞。然而，这一假设尚未得到检验。我们构建了一个重组MCMV，其编码病毒必需基因IE 3中造血特异性miRNA miR-142- 3 p的靶位点。这种病毒传播不良的唾液腺鼻内或足垫感染，但没有以下腹腔内感染C57 BL/6小鼠，表明造血细胞的传播是必不可少的特定感染途径。值得注意的是，NK细胞或T细胞的耗竭恢复了这种病毒在C57 BL/6小鼠鼻内感染后的传播，而传播在BALB/c小鼠中正常发生，这些小鼠缺乏对MCMV的强NK细胞控制。这些数据表明，细胞介导的免疫是负责限制MCMV造血细胞介导的传播。感染的造血细胞通过调节I类MHC和NKG 2D配体的三种免疫逃避基因（m04、m06和m152）避免细胞介导的免疫。缺乏这3个基因的MCMV传播到唾液腺很差，除非NK细胞被耗尽，但也不能在鼻粘膜或唾液腺中持续复制，除非CD 8 + T细胞被耗尽。令人惊讶的是，鼻内感染后引发的CD 8 + T细胞需要CD 4 + T细胞帮助扩增并发挥功能。总之，我们的数据表明，MCMV可以使用造血细胞依赖性和非依赖性的手段传播鼻内感染后，细胞介导的免疫反应限制传播感染的造血细胞，这是保护从NK细胞在传播过程中的病毒免疫逃避。相反，粘膜组织内的病毒复制依赖于T细胞的逃避。巨细胞病毒（CMV）是免疫功能低下个体的常见病因，也是导致新生儿疾病的先天性感染的常见病因。病毒被认为主要通过粘膜屏障组织进入，如口腔和鼻粘膜。然而，目前尚不清楚病毒如何逃离这些屏障组织到达远处的部位。在这项研究中，我们使用了CMV感染的小鼠模型。我们的数据说明了免疫系统和病毒感染“骨髓细胞”之间的复杂平衡，骨髓细胞通常被认为是感染后携带病毒的机体。特别是，我们的数据表明，感染部位的强大免疫反应迫使病毒依赖于骨髓细胞来逃避感染部位。此外，需要设计用于逃避这些免疫反应的病毒基因，以在病毒传播到远处的过程中和之后保护病毒。总之，这项工作揭示了在CMV感染粘膜组织和传播到身体的远端部位期间的免疫控制和病毒存活的机制。
Cytomegalovirus (CMV) causes clinically important diseases in immune compromised and immune immature individuals. Based largely on work in the mouse model of murine (M)CMV, there is a consensus that myeloid cells are important for disseminating CMV from the site of infection. In theory, such dissemination should expose CMV to cell-mediated immunity and thus necessitate evasion of T cells and NK cells. However, this hypothesis remains untested. We constructed a recombinant MCMV encoding target sites for the hematopoietic specific miRNA miR-142-3p in the essential viral gene IE3. This virus disseminated poorly to the salivary gland following intranasal or footpad infections but not following intraperitoneal infection in C57BL/6 mice, demonstrating that dissemination by hematopoietic cells is essential for specific routes of infection. Remarkably, depletion of NK cells or T cells restored dissemination of this virus in C57BL/6 mice after intranasal infection, while dissemination occurred normally in BALB/c mice, which lack strong NK cell control of MCMV. These data show that cell-mediated immunity is responsible for restricting MCMV to hematopoietic cell-mediated dissemination. Infected hematopoietic cells avoided cell-mediated immunity via three immune evasion genes that modulate class I MHC and NKG2D ligands (m04, m06 and m152). MCMV lacking these 3 genes spread poorly to the salivary gland unless NK cells were depleted, but also failed to replicate persistently in either the nasal mucosa or salivary gland unless CD8+ T cells were depleted. Surprisingly, CD8+ T cells primed after intranasal infection required CD4+ T cell help to expand and become functional. Together, our data suggest that MCMV can use both hematopoietic cell-dependent and -independent means of dissemination after intranasal infection and that cell mediated immune responses restrict dissemination to infected hematopoietic cells, which are protected from NK cells during dissemination by viral immune evasion. In contrast, viral replication within mucosal tissues depends on evasion of T cells. Cytomegalovirus (CMV) is a common cause of disease in immune compromised individuals as well as a common cause of congenital infections leading to disease in newborns. The virus is thought to enter primarily via mucosal barrier tissues, such as the oral and nasal mucosa. However, it is not clear how the virus escapes these barrier tissues to reach distant sites. In this study, we used a mouse model of CMV infection. Our data illustrate a complex balance between the immune system and viral infection of “myeloid cells”, which are most commonly thought to carry the virus around the body after infection. In particular, our data suggest that robust immune responses at the site of infection force the virus to rely on myeloid cells to escape the site of infection. Moreover, viral genes designed to evade these immune responses were needed to protect the virus during and after its spread to distant sites. Together, this work sheds light on the mechanisms of immune control and viral survival during CMV infection of mucosal tissues and spread to distant sites of the body.
登录
查看更多内容
影响因子：
30.3
作者：
Daley-Bauer LP;Roback LJ;Wynn GM;Mocarski ES
通讯作者：
Mocarski ES
影响因子：
5.4
作者：
Angulo, A;Ghazal, P;Messerle, M
通讯作者：
Messerle, M
影响因子：
6.4
作者：
Farrell，Helen E.;Lawler，Clara;Stevenson，Philip G.
通讯作者：
Stevenson，Philip G.
DOI：
10.1073/pnas.1808849116
发表时间：
2019-03-05
影响因子：
11.1
作者：
Cullen, Jolie G.;McQuilten, Hayley A.;Turner, Stephen J.
通讯作者：
Turner, Stephen J.
影响因子：
4.4
作者：
Gold, MC;Munks, MW;Hill, AB
通讯作者：
Hill, AB