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Molecular genetic characterization of the distal NKC recombination hotspot and putative murine CMV resistance control locus

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Abstract

The NK gene complex (NKC) controls murine cytomegalovirus (MCMV) immunity through Cmv1-dependent natural killer (NK) cell responses. Ly49H expression correlates with Cmv1 phenotypes in different inbred strains, is required for MCMV resistance in C57BL/6 (B6) mice, and its interaction with the MCMV encoded m157 protein leads to NK cell-mediated destruction of virus-infected cells. However, genetic mapping studies have previously indicated that Cmv1 should reside in the D6Wum9–16 NKC interval, distal to Ly49h. Since these data suggested that multiple NKC-linked loci could regulate viral immunity, a putative MCMV resistance control (Mrc) locus was pinpointed to within the D6Wum9–16 interval on a NKC-aligned bacterial artificial chromosome (BAC). Sequence analysis of BAC 151 revealed several novel G-protein coupled receptor genes, an HMG-1 remnant and many additional polymorphic microsatellites that were useful in determining the minimal genetic interval for the Mrc locus. Moreover, comparison of B6, BALB/c, A/J and recombinant Mrc alleles restricted the genetic interval to approximately 470 bp and showed that it was also a hotspot for recombination. MCMV challenge of novel NKC recombinant mice demonstrated that Mrc B6 was not required for MCMV resistance nor could it directly complement the Ly49 BALB haplotype to rescue MCMV susceptibility. Taken together, these data show that while Mrc apparently guides recombination, Ly49H expression is sufficient for MCMV resistance in B6 mice. A direct role for Mrc B6 in virus resistance is excluded in the novel mice.

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Acknowledgements

We thank Kim Marlotte and Lolita Bland for animal care and breeding. This work was supported by NIH grants to M.G.B. (AI50072) and to W.M.Y. who is an investigator of the Howard Hughes Medical Institute. M.G.B. also received support from the Department of Internal Medicine and the Beirne Carter Center, University of Virginia. A.A.S. is supported by grants 990646 and 139178 from the National Health and Medical Research Council of Australia.

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Authors and Affiliations

  1. Department of Microbiology, University of Western Australia, 6907, Nedlands, Western Australia, Australia

    Anthony A. Scalzo

  2. Department of Internal Medicine, Division of Rheumatology and Immunology, University of Virginia School of Medicine, Box 800412, Charlottesville, VA 22908, USA

    Roy Wheat, Patricia Clark, Naomi Dong & Michael G. Brown

  3. Division of Rheumatology, Howard Hughes Medical Institute, Washington University School of Medicine, Box 8045, St. Louis, MO 63110, USA

    Chad Dubbelde, Laurie Stone, Ying Du, Janis Stoll, Wayne M. Yokoyama & Michael G. Brown

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  1. Anthony A. Scalzo
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  2. Roy Wheat
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  3. Chad Dubbelde
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  4. Laurie Stone
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  5. Patricia Clark
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  7. Naomi Dong
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  9. Wayne M. Yokoyama
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  10. Michael G. Brown
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Corresponding author

Correspondence to Michael G. Brown.

Additional information

The nucleotide sequence data reported in this paper were assigned GenBank accession numbers AF462604, AY145449 and AY145450.

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Scalzo, A.A., Wheat, R., Dubbelde, C. et al. Molecular genetic characterization of the distal NKC recombination hotspot and putative murine CMV resistance control locus. Immunogenetics 55, 370–378 (2003). https://doi.org/10.1007/s00251-003-0591-8

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  • DOI: https://doi.org/10.1007/s00251-003-0591-8

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