Cytomegalovirus determinant of replication in salivary glands

Abstract

Murine cytomegalovirus carrying a deletion mutation disrupting the expression of a gene dispensable for growth in cultured cells was found to disseminate poorly in the mouse. The mutation resulted in a dramatic decrease in the expression of a 1.5-kb major and a 1.8-kb minor 1a transcript from a region adjacent to the ie2 gene in the viral genome. Nucleotide sequence determination indicated that 323 bp, including a predicted polyadenylation signal, was deleted from this 1a gene. In cultured cells, the plaque morphology and growth characteristics of the mutant were similar to those of parental or rescued wild-type viruses. Following intraperitoneal inoculation of BALB/c mice, growth of the mutant in the salivary gland was dramatically reduced 10,000-fold, while growth in the liver and spleen was not dramatically affected. The 13 gene was thus denoted sggl (salivary gland growth gene 1). Neither intranasal infection nor direct inoculation into the salivary glands completely overcame the restriction of growth in this organ, suggesting that the sggl gene encoded a determinant of tissue tropism. To investigate the impact of the sggl mutation on virus dissemination via the blood, the virus titer in peripheral blood leukocytes was determined. No difference was found between the sggl mutant and rescued wild-type virus. Thus, murine cytomegalovirus sggl gene products appear to be involved in entry or replication of virus in salivary gland cells.

Murine cytomegalovirus with a deletion of genes spanning HindIII-J and -I displays altered cell and tissue tropism

“…The sizes of the deletions within the recombinant viruses were inversely correlated with the extent of replication of the mutants in salivary glands, suggesting that multiple genes may be involved in salivary gland growth. It appears from these data and those of others (9,35,40) that mutations throughout the HindIII-J and -I regions affect salivary gland growth, as optimal growth in this tissue appears to be exquisitely sensitive to mutations within this region. In addition, the mere presence of the ␤-glu gene may affect replication of MCMV in the salivary gland (60).…”

“…It is unclear at this time if RV7 is unique among HindIII-J and -I mutants in its hampered ability to replicate in the IC-21 cell line. However, preliminary data indicate that MCMV HindIII-J mutants disrupted in ORF m134 (RQ401), m136 (RM874), or M139 (RM873) (40,65) grow to high titers in IC-21 cells, as does RV6, in which m137 and m138 are deleted. Confirmation of efficient replication of RM873 (65) would imply that gene products regulating growth of RV7 in the IC-21 macrophage cell line are encoded in ORFs M140 and/or M141.…”

Cytomegalovirus exploits IL-10–mediated immune regulation in the salivary glands

“…Interestingly, MCMV alters the microarchitecture of the spleen by selective depression of CCL21 chemokine mRNA expression, which alters T cell traffi cking within the spleen (41). Mutations in the viral genes M155 (42), M35 (43), or M133 (44,45) abrogate replication in the salivary glands, although the role of these genes in promoting IL-10expressing T cells is not understood. Of signifi cance is the presence of viral IL-10 orthologs in primate CMV (46,47), Epstein-Barr virus (48), and equine herpesvirus 2 (49).…”

The pathogenicity of cytomegalovirus

“…Natural killer (NK) cells help to restrict the viral replication in some organs during this E phase [87^92]. After the onset of the speci¢c immune response at 6^9 days post inoculation, virus is cleared e¤ciently from most organs but continues to actively replicate in the salivary glands for at least 4 weeks regardless of the mouse strain infected [93,94].…”