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

Nature Genetics volume 28, pages 42–45 (2001)Cite this article

Abstract

Cytomegalovirus is the leading cause of congenital viral disease and the most important opportunistic infection in immunocompromised patients1,2. 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 targets3,4,5. 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 genes8, 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 molecules13,14,15. 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 genes15,16,17, 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).

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Figure 1: Genetic analysis of MCMV susceptibility in the BXD-8 strain.
Figure 2: In vivo complementation of susceptibility to MCMV infection in the BXD-8 strain.
Figure 3: Location of Cmv1 and marker loci used for STS content and haplotype analysis in the BXD-8 strain.
Figure 4: Physical mapping in the region of Klra8.
Figure 5: Expression analysis of the Klra gene cluster.

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Acknowledgements

We thank C. Depatie, A. Chalifour and S. Lemieux for initial characterization of the BXD-8 strain; J.-A. Herbrick and S. Scherer for facilitating BAC clones; P. Bertrand for assistance with the artwork; J. Webb, D. Bulman and R. Kothary for critical reading of the manuscript; and D. Malo for discussions. This work was supported by grants from the Canadian Institutes of Health Research (CIHR) and a research award from the University of Ottawa. S.H. Lee is supported by an Ontario Graduate Scholarship. P. Gros is a Senior Scientist of CIHR and an International Research Scholar of the Howard Hughes Medical Research Institute. S.M. Vidal is a scholar of CIHR.

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Authors and Affiliations

  1. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada

    Seung-Hwan Lee, Sonia Girard, Denis Macina, Maria Busà, Ahmed Zafer & Silvia M. Vidal

  2. Galileo Genomics Inc., Montréal, Québec, Canada

    Abdelmajid Belouchi

  3. Department of Biochemistry, McGill University, Montréal, Québec, Canada

    Philippe Gros

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Correspondence to Silvia M. Vidal.

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Lee, SH., Girard, S., Macina, D. et al. Susceptibility to mouse cytomegalovirus is associated with deletion of an activating natural killer cell receptor of the C-type lectin superfamily. Nat Genet 28, 42–45 (2001). https://doi.org/10.1038/ng0501-42

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