Intraocular human cytomegaloviruses of ocular diseases are distinct from those of viremia and are capable of escaping from innate and adaptive immunity by exploiting HLA-E-mediated peripheral and central tolerance.
Intraocular human cytomegaloviruses of ocular diseases are distinct from those of viremia and are capable of escaping from innate and adaptive immunity by exploiting HLA-E-mediated peripheral and central tolerance.
复制标题
DOI：
10.3389/fimmu.2022.1008220
复制
发表时间：
2022
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
--
作者：
人巨细胞病毒（HCMV）感染发展成CMV疾病，其导致局部器官中的各种形式的表现。CMV-视网膜炎是CMV疾病的一种形式，在外周循环中的病毒进入眼睛后，在具有CMV-病毒血症的免疫受损宿主中发展。在HCMV基因组中，UL 40基因的广泛多样性产生了肽序列，当加载到HLA-E上时调节NK细胞效应子功能，随后被NKG 2A和NKG 2C受体识别。值得注意的是，一些HCMV毒株携带编码与特定HLA-A和HLA-C同种异型的信号肽序列相同的肽序列的UL 40基因，这使得这些CMV毒株能够逃避HLA-E限制性CD 8 +T细胞应答。UL 40序列的变异主要在CMV病毒血症病例的外周血中进行了研究。在这项研究中，我们试图调查如何从CMV感染发展成眼部CMV疾病。对77例临床病例的眼内液和外周血中CMV基因序列进行了比较。UL 40信号肽序列更多样化，与眼内液相比，CMV病毒血症血液中通常存在多个序列。与仅在外周血中鉴定的那些相比，来自眼内HCMV的UL 40衍生肽诱导了显著更强的NK细胞抑制。存在于眼内液中的HCMV限于携带对应于宿主HLA I类前导肽序列的UL 40肽序列的那些，而仅在外周血中发现的来自HCMV的UL 40衍生肽与任何HLA I类同种异型不同。总体而言，我们对CMV视网膜炎的分析推断，具有与宿主HLA信号肽序列匹配的UL 40信号序列的特定HCMV株是那些穿过血眼屏障进入眼内空间的HCMV株。UL 40肽库在所有眼部CMV疾病的眼内液中是相同的，无论宿主免疫状态如何，这意味着病毒类型可能是眼部CMV疾病发展的共同决定因素。因此，我们提出了一种机制，眼部CMV疾病的发展，其中特定的HCMV类型在血液中利用外周和中央HLA-E介导的耐受机制，从而逃避先天性和适应性免疫的抗病毒反应。
Human cytomegalovirus (HCMV) infections develop into CMV diseases that result in various forms of manifestations in local organs. CMV-retinitis is a form of CMV disease that develops in immunocompromised hosts with CMV-viremia after viruses in the peripheral circulation have entered the eye. In the HCMV genome, extensive diversification of the UL40 gene has produced peptide sequences that modulate NK cell effector functions when loaded onto HLA-E and are subsequently recognized by the NKG2A and NKG2C receptors. Notably, some HCMV strains carry UL40 genes that encode peptide sequences identical to the signal peptide sequences of specific HLA-A and HLA-C allotypes, which enables these CMV strains to escape HLA-E-restricted CD8+T cell responses. Variations in UL40 sequences have been studied mainly in the peripheral blood of CMV-viremia cases. In this study, we sought to investigate how ocular CMV disease develops from CMV infections. CMV gene sequences were compared between the intraocular fluids and peripheral blood of 77 clinical cases. UL40 signal peptide sequences were more diverse, and multiple sequences were typically present in CMV-viremia blood compared to intraocular fluid. Significantly stronger NK cell suppression was induced by UL40-derived peptides from intraocular HCMV compared to those identified only in peripheral blood. HCMV present in intraocular fluids were limited to those carrying a UL40 peptide sequence corresponding to the leader peptide sequence of the host’s HLA class I, while UL40-derived peptides from HCMV found only in the peripheral blood were disparate from any HLA class I allotype. Overall, our analyses of CMV-retinitis inferred that specific HCMV strains with UL40 signal sequences matching the host’s HLA signal peptide sequences were those that crossed the blood–ocular barrier to enter the intraocular space. UL40 peptide repertoires were the same in the intraocular fluids of all ocular CMV diseases, regardless of host immune status, implying that virus type is likely to be a common determinant in ocular CMV disease development. We thus propose a mechanism for ocular CMV disease development, in which particular HCMV types in the blood exploit peripheral and central HLA-E-mediated tolerance mechanisms and, thus, escape the antivirus responses of both innate and adaptive immunity.
影响因子：
5.6
作者：
Yawata N;Shirane M;Woon K;Lim X;Tanaka H;Kawano YI;Yawata M;Chee SP;Siak J;Sonoda KH
通讯作者：
Sonoda KH