TY - JOUR
T1 - The m15 locus of murine cytomegalovirus modulates natural killer cell responses to promote dissemination to the salivary glands and viral shedding
AU - Chan, Baca
AU - Arapović, Maja
AU - Masters, Laura L.
AU - Rwandamuiye, Francois
AU - Jonjić, Stipan
AU - Smith, Lee M.
AU - Redwood, Alec J.
PY - 2021/7
Y1 - 2021/7
N2 - As the largest herpesviruses, the 230 kb genomes of cytomegaloviruses (CMVs) have increased our understanding of host immunity and viral escape mechanisms, although many of the annotated genes remain as yet uncharacterised. Here we identify the m15 locus of murine CMV (MCMV) as a viral modulator of natural killer (NK) cell immunity. We show that, rather than discrete transcripts from the m14, m15 and m16 genes as annotated, there are five 3′-coterminal transcripts expressed over this region, all utilising a consensus polyA tail at the end of the m16 gene. Functional inactivation of any one of these genes had no measurable impact on viral replication. However, disruption of all five transcripts led to significantly attenuated dissemination to, and replication in, the salivary glands of multiple strains of mice, but normal growth during acute infection. Disruption of the m15 locus was associated with heightened NK cell responses, including enhanced proliferation and IFNγ production. Depletion of NK cells, but not T cells, rescued salivary gland replication and viral shedding. These data demonstrate the identification of multiple transcripts expressed by a single locus which modulate, perhaps in a concerted fashion, the function of antiviral NK cells.
AB - As the largest herpesviruses, the 230 kb genomes of cytomegaloviruses (CMVs) have increased our understanding of host immunity and viral escape mechanisms, although many of the annotated genes remain as yet uncharacterised. Here we identify the m15 locus of murine CMV (MCMV) as a viral modulator of natural killer (NK) cell immunity. We show that, rather than discrete transcripts from the m14, m15 and m16 genes as annotated, there are five 3′-coterminal transcripts expressed over this region, all utilising a consensus polyA tail at the end of the m16 gene. Functional inactivation of any one of these genes had no measurable impact on viral replication. However, disruption of all five transcripts led to significantly attenuated dissemination to, and replication in, the salivary glands of multiple strains of mice, but normal growth during acute infection. Disruption of the m15 locus was associated with heightened NK cell responses, including enhanced proliferation and IFNγ production. Depletion of NK cells, but not T cells, rescued salivary gland replication and viral shedding. These data demonstrate the identification of multiple transcripts expressed by a single locus which modulate, perhaps in a concerted fashion, the function of antiviral NK cells.
KW - Coterminal transcription
KW - Cytomegalovirus
KW - Immune evasion
KW - M15
KW - Natural killer
KW - Saliva shedding
KW - Salivary gland
UR - http://www.scopus.com/inward/record.url?scp=85111144821&partnerID=8YFLogxK
U2 - 10.3390/pathogens10070866
DO - 10.3390/pathogens10070866
M3 - Article
C2 - 34358016
AN - SCOPUS:85111144821
SN - 2076-0817
VL - 10
JO - Pathogens
JF - Pathogens
IS - 7
M1 - 866
ER -