Cytomegalovirus evasion of innate immunity by subversion of the NKR-P1B:Clr-b missing-self axis.
Cytomegaloviruses are known to encode several gene products that function to subvert MHC-dependent immune recognition. Here we characterize a rat cytomegalovirus (RCMV) C-type lectin-like (RCTL) gene product with homology to the Clr ligands for the NKR-P1 receptors. RCMV infection rapidly extinguished host Clr-b expression, thereby sensitizing infected cells to killing by natural killer (NK) cells. However, the RCTL protein functioned as a decoy ligand to protect infected cells from NK killing via direct interaction with the NKR-P1B inhibitory receptor. In vivo, an RCTL mutant virus displayed diminished virulence in an NK-dependent and strain-specific manner, suggesting that host NKR-P1 polymorphisms have evolved to avert the viral decoy mechanism while maintaining Clr-b recognition to preserve self tolerance. These findings reveal a unique strategy adopted by cytomegaloviruses to evade MHC-independent self-nonself discrimination. The existence of lectin-like genes in several poxviruses suggests that this may represent a common theme for viral evasion of innate immunity.
Voigt
Sebastian
S
Division of Viral Infections, Robert Koch Institute, Nordufer 20, 13353 Berlin, Germany. voigts@rki.de
Mesci
Aruz
A
Ettinger
Jakob
J
Fine
Jason H
JH
Chen
Peter
P
Chou
Wayne
W
Carlyle
James R
JR
D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D058286:Calcitonin Receptor-Like Protein; D002460:Cell Line; D005260:Female; D005786:Gene Expression Regulation; D016679:Genome, Viral / Q000235:genetics; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D008969:Molecular Sequence Data; D018146:Muromegalovirus / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D010802:Phylogeny; D051381:Rats; D018003:Receptors, Calcitonin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000378:metabolism*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D053586:Virus Internalization
C545578:CALCRL protein, human; D058286:Calcitonin Receptor-Like Protein; C545580:Calcrl protein, rat; C479632:Klrb1b protein, rat; D037181:Lectins, C-Type; D008024:Ligands; D018003:Receptors, Calcitonin; D011971:Receptors, Immunologic