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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

Authors :
Mariko Shirane
Nobuyo Yawata
Daisuke Motooka
Kensuke Shibata
Seik-Soon Khor
Yosuke Omae
Toshikatsu Kaburaki
Ryoji Yanai
Hisashi Mashimo
Satoshi Yamana
Takako Ito
Akira Hayashida
Yasuo Mori
Akihiko Numata
Yusuke Murakami
Kohta Fujiwara
Nobuyuki Ohguro
Mayumi Hosogai
Masato Akiyama
Eiichi Hasegawa
Michael Paley
Atsunobu Takeda
Katsumi Maenaka
Koichi Akashi
Wayne M. Yokoyama
Katsushi Tokunaga
Makoto Yawata
Koh-Hei Sonoda
Source :
Frontiers in Immunology, Vol 13 (2022)
Publication Year :
2022
Publisher :
Frontiers Media S.A., 2022.

Abstract

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.

Details

Language :
English
ISSN :
16643224
Volume :
13
Database :
Directory of Open Access Journals
Journal :
Frontiers in Immunology
Publication Type :
Academic Journal
Accession number :
edsdoj.63bb0ba05e554e95ac750a000d29d750
Document Type :
article
Full Text :
https://doi.org/10.3389/fimmu.2022.1008220