Susceptibility to mouse cytomegalovirus is associated with deletion of an activating natural killer cell receptor of the C-type lectin superfamily

Abstract

Cytomegalovirus is the leading cause of congenital viral disease and the most important opportunistic infection in immunocompromised patients. We have used a mouse experimental infection model (MCMV) to study the genetic parameters of host/virus interaction. Susceptibility to infection with MCMV is controlled by Cmv1, a chromosome 6 locus that regulates natural killer (NK) cell activity against virally infected targets. Here, we use a positional cloning strategy to isolate the gene mutated at the Cmv1 locus. Cmv1 maps within a 0.35-cM interval defined by markers D6Ott8 and D6Ott115, which corresponds to a physical distance of 1.6 Mb (refs. 6-8). A transcript map of the region identified 19 genes, including members of the killer cell lectin-like receptor family a (Klra, formerly Ly49; refs. 9-12), which encode inhibitory or activating NK cell receptors that interact with MHC class I molecules. Klra genes have different copy numbers and genomic organization, and are highly polymorphic among inbred strains, making it difficult to distinguish between normal allelic variants and distinct Klra genes, or possible mutations associated with Cmv1. The recombinant inbred strain BXD-8/Ty (BXD-8; ref. 18), derived from Cmv1r C57BL/6 (B6, resistant) and Cmv1s DBA/2 (susceptible), is of particular interest because it is highly susceptible to MCMV infection despite having a B6 haplotype at Cmv1. We determined that MCMV susceptibility in BXD-8 is associated with the deletion of Klra8 (formerly Ly49h).

Natural killer cell memory in infection, inflammation and cancer

“…The importance of the LY49H receptor in NK cell-mediated resistance against MCMV was first revealed by classic genetic studies 25,26 and by experiments using a neutralizing LY49H-specific antibody 27 . The mechanism by which this receptor prevented disease had remained unclear.…”

Sweet Is the Memory of Past Troubles: NK Cells Remember

“…In a similar manner, mouse CMV (MCMV) has coevolved with its host for long enough to impact the NK receptor repertoire. NK cells from C57BL/6 (B6) mice carry a germline-encoded activating receptor, Ly49H, that specifically recognizes the MCMV-encoded protein m157 (Lee et al 2001;Arase et al 2002;Dokun et al 2001;Smith et al 2002). The MCMV model has established a critical role for NK cells in controlling host resistance to infection (Scalzo et al 1992), which is, in part, driven by recognition of m157 by Ly49H.…”

Complex genetic control of susceptibility to malaria in mice

“…These genes can then be localized in linkage studies, and in certain cases, can be identified by transcription mapping and positional cloning. [32][33][34][35][36] The mouse is the experimental model of choice for this type of analysis for the following reasons: (1) the virulence status of the infectious agent, as well as the dose, and route of infection can be tightly controlled, thereby reducing microbial-induced variability; (2) large numbers of wild-type isolates and mutant stocks of mice are available in an inbred status; (3) informative segregating animals can be generated in large numbers for linkage mapping and positional cloning; (4) the sequence of the mouse genome is soon to be completed, providing a compendium of candidate genes for a particular region; (5) null alleles at candidate genes can be readily obtained by gene targeting; and (6) 37,38 The symptoms and pathology associated with blood-stage infection of mice with P. chabaudi , while not exactly mirroring those associated with human malaria, are similar enough that murine models have been useful in defining the immunological basis of some of the pathology in man (reviewed in Mohan and Stevenson 5 ). Many blood-stage antigens of this parasite are analogous to those of P. falciparum.…”