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NK gene complex and chromosome 19 loci enhance MHC resistance to murine cytomegalovirus infection

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Abstract

An H-2k MHC locus is critical for murine cytomegalovirus (MCMV) resistance in MA/My mice and virus control is abolished if H-2k is replaced with H-2b MHC genes from MCMV-susceptible C57L mice. Yet, H-2k resistance varies with genetic background; thus, modifiers of virus resistance must exist. To identify non-MHC resistance loci, spleen and liver MCMV levels and genome-wide genotypes were assessed in (C57L × MA/My) and (MA/My × C57L) F2 offspring (representing 550 meioses). Significantly, a non-Mendelian frequency of MHC genotypes was observed for offspring of the latter cross. Quantitative trait loci (QTL) and their interaction potential in MCMV resistance were assessed in R/qtl; QTL on chromosomes 17, 6, and 19 affected MCMV levels in infected animals. A chromosome 6 QTL was linked with the NK gene complex and acted in an additive fashion with an H-2k MHC QTL to mitigate spleen MCMV levels. We provide biological confirmation that this chromosome 6 QTL provided MCMV control independent of H-2k via NK cells. Importantly, both chromosome 6 and 19 QTLs contribute to virus control independent of H-2k. Altogether, MHC and non-MHC MCMV-resistance QTL contribute in early resistance to MCMV infection in this genetic system.

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Acknowledgments

We thank Corinne Abalos and Susan Alejandra Sainz for technical assistance. This work was supported by National Institutes of Health (NIH) National Institute of Allergy and Infectious Disease Grant R01 AI050072. M.D.S was supported by the NIH Interdisciplinary Training Program in Immunology (5T32 AI07496) and the NIH Biotechnology Training Program (T32 GM08715).

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Authors and Affiliations

  1. Department of Microbiology, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA

    Michael D. Stadnisky & Michael G. Brown

  2. Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA

    Ani Manichaikul

  3. Department of Public Health Sciences, Division of Biostatistics and Epidemiology, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA

    Ani Manichaikul

  4. Department of Medicine, Division of Nephrology, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA

    Alyssa G. Lundgren & Michael G. Brown

  5. Beirne B. Carter Center for Immunology Research, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA

    Michael G. Brown

  6. Department of Medicine, Beirne B. Carter Center for Immunology Research, University of Virginia Health System, Box 801386, 345 Crispell Drive, Charlottesville, VA, 22908, USA

    Michael G. Brown

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  1. Michael D. Stadnisky
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  2. Ani Manichaikul
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  3. Alyssa G. Lundgren
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  4. Michael G. Brown
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Correspondence to Michael G. Brown.

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Stadnisky, M.D., Manichaikul, A., Lundgren, A.G. et al. NK gene complex and chromosome 19 loci enhance MHC resistance to murine cytomegalovirus infection. Immunogenetics 61, 755–764 (2009). https://doi.org/10.1007/s00251-009-0400-0

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