Functional analysis of M139, a pathogenesis factor of mouse cytomegalovirus

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Cytomegalovirus (CMV) is a common herpes virus that infects almost 60% of the adult population in the United States. It is transmitted via body fluids: saliva, tears, urine, stool, semen, and breast milk. Once a person is infected, it can be retained in the body for life with rarely any symptoms. CMV may cause several complications like retinitis or hepatitis in immunocompromised people and hearing loss or mental retardation in neonates. CMV is host specific meaning that human cytomegalovirus (HCMV) can only infect humans. For this reason, mouse cytomegalovirus (MCMV) is often studied in the mouse model for understanding the function of conserved and pathogenically important gene families. The M139, M140 and M141 genes in MCMV belong to the US22 gene family, members of which play important roles in pathogenesis. It has been shown that the deletion of any one of the M139, M140, and M141 genes leads to replication impairment of MCMV in macrophages. While the M140 protein is required for stable viral gene encapsidation in macrophages, the role of the M139 protein in virus replication is still unknown. Dr. Clive Sweet’s lab showed that a mutant virus with a C-terminal truncation of 79 amino acids in M139 replicates normally at 37°C in both fibroblasts and macrophages but the replication is impaired at 40°C in fibroblasts. We have determined that this mutant virus is also temperature sensitive in a neuroblastoma cells indicating that this defect is not restricted to fibroblast cells. The combination of lack of a temperature sensitive defect in ΔM140 and ΔM141, the coprecipitation of pM140 with the pM139trun, and that the defect occurs after capsid assembly, unlike ΔM140, supports that the pM139 has a function separable from the complex with pM140-pM141. Although the stability of the MutM139 infectious particle is not altered, higher number of non-infectious MutM139 particles are produced from infected cells at 40˚C than at 37˚C. The most likely possibility for the production of large number of non-infectious MutM139 particles would be a defect in the incorporation of one or more tegument proteins, possibly including pM139, into the virus particles.

Temperature sensitive, Mouse cytomegalovirus