201. The murine cytomegalovirus chemokine homolog, m131/129, is a determinant of viral pathogenicity
- Author
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Peter Fleming, Nicholas Davis-Poynter, Eloise H. Densley, John Papadimitriou, Helen E. Farrell, Geoffrey Shellam, and Mariapia A. Degli-Esposti
- Subjects
CD4-Positive T-Lymphocytes ,Muromegalovirus ,Chemokine ,Transcription, Genetic ,RNA Splicing ,Molecular Sequence Data ,Immunology ,Inflammation ,CD8-Positive T-Lymphocytes ,Virus Replication ,Microbiology ,Salivary Glands ,Virus ,Cell Line ,Proinflammatory cytokine ,Mice ,Open Reading Frames ,Viral Proteins ,Immune system ,Virology ,medicine ,Animals ,Interferon gamma ,Amino Acid Sequence ,Recombination, Genetic ,Mice, Inbred BALB C ,Base Sequence ,biology ,Herpesviridae Infections ,Fibroblasts ,biology.organism_classification ,Killer Cells, Natural ,Viral replication ,Chemokines, CC ,Insect Science ,DNA, Viral ,biology.protein ,Pathogenesis and Immunity ,medicine.symptom ,medicine.drug - Abstract
Chemokines are important mediators of the early inflammatory response to infection and modify a wide range of host immune responses. Functional homologs of cellular chemokines have been identified in a number of herpesviruses, suggesting that the subversion of the host chemokine response contributes to the pathogenesis of these viruses. Transcriptional and reverse transcription-PCR analyses demonstrated that the murine cytomegalovirus (MCMV) chemokine homolog, m131, was spliced at the 3′ end to the adjacent downstream open reading frame, m129, resulting in a predicted product of 31 kDa, which is significantly larger than most known chemokines. The in vivo impact of m131/129 was investigated by comparing the replication of MCMV mutants having m131/129 deleted (Δm131/129) with that of wild-type (wt) MCMV. Our studies demonstrate that both wt and Δm131/129 viruses replicated to equivalent levels during the first 2 to 3 days following in vivo infection. However, histological studies demonstrated that the early inflammatory response elicited by Δm131/129 was reduced compared with that of wt MCMV. Furthermore, the Δm131/129 mutants failed to establish a high-titer infection in the salivary glands. These results suggest that m131/129 possesses proinflammatory properties in vivo and is important for the dissemination of MCMV to or infection of the salivary gland. Notably, the Δm131/129 mutants were cleared more rapidly from the spleen and liver during acute infection compared with wt MCMV. The accelerated clearance of the mutants was dependent on NK cells and cells of the CD4 + CD8 + phenotype. These data suggest that m131/129 may also contribute to virus mechanisms of immune system evasion during early infection, possibly through the interference of NK cells and T cells.