Natural Killer Cell Evasion Is Essential for Infection by Rhesus Cytomegalovirus

PLoS Pathogens

Christine L. Schneider¹  Amy W. Hudson²  Amruta Bhusari³  Daniel Malouli³  Seongkyung Seo³  Jennie L. Womack³  Abigail B. Ventura³  Krystal M. Jeffries³  Michael K. Axthelm³  Alfred W. Legasse³  Elizabeth R. Sturgill³  Benjamin J. Burwitz³  Louis J. Picker³  Marieke C. Verweij³  Klaus Früh³  Scott G. Hansen³  Jonah B. Sacha³ 

[1] Department of Life Sciences, Carroll University, Waukesha, Wisconsin, United States of America;Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America;Vaccine and Gene Therapy Institute, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon, United States of America

关键词: T cells;    NK cells;    Cytotoxic T cells;    Flow cytometry;    Fibroblasts;    Cytomegalovirus infection;    Human cytomegalovirus;    Immunoprecipitation;   

DOI  :  10.1371/journal.ppat.1005868

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

The natural killer cell receptor NKG2D activates NK cells by engaging one of several ligands (NKG2DLs) belonging to either the MIC or ULBP families. Human cytomegalovirus (HCMV) UL16 and UL142 counteract this activation by retaining NKG2DLs and US18 and US20 act via lysomal degradation but the importance of NK cell evasion for infection is unknown. Since NKG2DLs are highly conserved in rhesus macaques, we characterized how NKG2DL interception by rhesus cytomegalovirus (RhCMV) impacts infection in vivo. Interestingly, RhCMV lacks homologs of UL16 and UL142 but instead employs Rh159, the homolog of UL148, to prevent NKG2DL surface expression. Rh159 resides in the endoplasmic reticulum and retains several NKG2DLs whereas UL148 does not interfere with NKG2DL expression. Deletion of Rh159 releases human and rhesus MIC proteins, but not ULBPs, from retention while increasing NK cell stimulation by infected cells. Importantly, RhCMV lacking Rh159 cannot infect CMV-naïve animals unless CD8+ cells, including NK cells, are depleted. However, infection can be rescued by replacing Rh159 with HCMV UL16 suggesting that Rh159 and UL16 perform similar functions in vivo. We therefore conclude that cytomegaloviral interference with NK cell activation is essential to establish but not to maintain chronic infection.

【 授权许可】

CC BY