The m15 locus of murine cytomegalovirus modulates natural killer cell responses and promotes dissemination to the salivary glands

Chan, B., Mitrovic, M., Masters, L., Jonjic, S., Shellam, G., Smith, L. and Redwood, A. (2016) The m15 locus of murine cytomegalovirus modulates natural killer cell responses and promotes dissemination to the salivary glands. In: International Congress of Immunology, 21 - 26 August 2016, Melbourne, VIC.

Abstract

Murine cytomegalovirus (MCMV) expresses in excess of 170 open reading frames (ORFs), many of which have unknown function. In addition, MCMV and other cytomegaloviruses exhibit complex gene regulation, including the expression of alternative splice variants, the use of alternative start sites and the expression of multiple mRNA species from a single locus. Such complex regulation can complicate the study of gene function. We show here that the MCMV locus composed of the m14, m15 and m16 ORFs expresses five overlapping mRNA transcripts that are all co-terminal with the predicted end of the m16 ORF. Functional inactivation of any one of these ORFs has no impact on viral replication. However, disruption of all five transcripts leads to an increase in viral virulence during acute infection. Whilst slight, this elevated virulence is reproducible in multiple mouse strains. Conversely, disruption of this locus also leads to significant viral attenuation, evidenced during chronic infection of the salivary glands. Attenuation at this site is likely due to reduced dissemination. This complex phenotype is associated with heightened natural killer (NK) cell responses, including enhanced proliferation and IFN production. Depletion of NK cells, but not T cells, rescues viraemia and salivary gland replication. These data demonstrate that multiple transcripts can modulate, perhaps in a concerted fashion, the function of anti-viral NK cells. In addition, these data highlight the need to define the transcriptional regulation of a viral locus before assigning gene function.

Item Type:	Conference Item
Murdoch Affiliation(s):	Institute for Immunology and Infectious Diseases
URI:	http://researchrepository.murdoch.edu.au/id/eprint/39110

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