The murine cytomegalovirus chemokine homolog, m131/129, is a determinant of viral pathogenicity.
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 (Deltam131/129) with that of wild-type (wt) MCMV. Our studies demonstrate that both wt and Deltam131/129 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 Deltam131/129 was reduced compared with that of wt MCMV. Furthermore, the Deltam131/129 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 Deltam131/129 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.
Departments of Microbiology, University of Western Australia, Nedlands, Western Australia 6907, Australia.
P
P
Fleming
N
N
Davis-Poynter
M
M
Degli-Esposti
E
E
Densley
J
J
Papadimitriou
G
G
Shellam
H
H
Farrell
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002460:Cell Line; D019742:Chemokines, CC / Q000235:genetics / Q000502:physiology*; D004279:DNA, Viral; D005347:Fibroblasts / Q000166:cytology / Q000821:virology; D006566:Herpesviridae Infections / Q000473:pathology; D007694:Killer Cells, Natural / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D018146:Muromegalovirus / Q000276:immunology / Q000472:pathogenicity* / Q000502:physiology; D016366:Open Reading Frames; D012326:RNA Splicing; D011995:Recombination, Genetic; D012469:Salivary Glands / Q000276:immunology / Q000821:virology; D014158:Transcription, Genetic; D014764:Viral Proteins / Q000235:genetics / Q000502:physiology*; D014779:Virus Replication
D019742:Chemokines, CC; D004279:DNA, Viral; D014764:Viral Proteins; C120682:m131 protein, Mouse cytomegalovirus 1