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

Department of Microbiology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
Immunogenetics (Impact Factor: 2.23). 10/2009; 61(11-12):755-64. DOI: 10.1007/s00251-009-0400-0
Source: PubMed


An H-2(k) MHC locus is critical for murine cytomegalovirus (MCMV) resistance in MA/My mice and virus control is abolished if H-2(k) is replaced with H-2(b) MHC genes from MCMV-susceptible C57L mice. Yet, H-2(k) 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 x MA/My) and (MA/My x C57L) F(2) 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-2(k) MHC QTL to mitigate spleen MCMV levels. We provide biological confirmation that this chromosome 6 QTL provided MCMV control independent of H-2(k) via NK cells. Importantly, both chromosome 6 and 19 QTLs contribute to virus control independent of H-2(k). Altogether, MHC and non-MHC MCMV-resistance QTL contribute in early resistance to MCMV infection in this genetic system.

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    • "Striking in this list of 49 variants is the significant number of genes associated with susceptibility to viral infections (Klra17, H2-D1, and H2-T3). Several of these are within the confidence interval of a QTL for resistance to murine cytomegalovirus in a cross between C57L/J and MA/My (Stadnisky et al. 2010). According to a previous study, disruptions in Ankrd17 are embryonic lethal (Hou et al. 2009). "
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    ABSTRACT: We sequenced the complete genome of the widely used C57L/J mouse inbred strain. With 40x average coverage we compared the C57L/J sequence with that of the C57BL/6J and identified many known, as well as novel private variants. This genome sequence adds another strain to the growing number of mouse inbred strains with complete genome sequences and is a valuable resource to the scientific community.
    G3-Genes Genomes Genetics 07/2014; 4(9). DOI:10.1534/g3.114.012997 · 3.20 Impact Factor
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    ABSTRACT: Ly49G and H-2 class I D(k) molecules are critical to natural killer cell-mediated viral control. To examine their contributions in greater depth, we established NK gene complex (NKC)/Ly49 congenic strains and a novel genetic model defined by MHC class I D(k) disparity in congenic and transgenic mouse strains. Generation and maintenance of Ly49 and H-2 class I select strains require efficient and reproducible genotyping assays for highly polygenic and polymorphic sequences. Thus, we coupled gene- and allele-specific PCR with high-resolution melt (HRM) analysis to discriminate Ly49g and H-2 class I D and K alleles in select strains and in the F(2) and backcross hybrid offspring of different genetic crosses. We show that HRM typing for these critical immune response genes is fast, accurate, and dependable. We further demonstrate that H-2 class I D HRM typing is competent to detect and quantify transgene copy numbers in different mice with distinct genetic backgrounds. Our findings substantiate the utility and practicality of HRM genotyping for highly related genes and alleles, even those belonging to clustered multigene families. Based on these findings, we envision that HRM is capable to interrogate and quantify gene- and allele-specific variations due to differential regulation of gene expression.
    Immunogenetics 07/2012; 64(8):633-40. DOI:10.1007/s00251-012-0630-4 · 2.23 Impact Factor
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    ABSTRACT: MHC class I D(k) and Ly49G2 (G2) inhibitory receptor-expressing NK cells are essential to murine CMV (MCMV) resistance in MA/My mice. Without D(k), G2(+) NK cells in C57L mice fail to protect against MCMV infection. As a cognate ligand of G2, D(k) licenses G2(+) NK cells for effector activity. These data suggested that D(k)-licensed G2(+) NK cells might recognize and control MCMV infection. However, a role for licensed NK cells in viral immunity is uncertain. We combined classical genetics with flow cytometry to visualize the host response to MCMV. Immune cells collected from individuals of a diverse cohort of MA/My × C57L offspring segregating D(k) were examined before infection and postinfection, including Ly49(+) NK subsets, receptor expression features, and other phenotypic traits. To identify critical NK cell features, automated analysis of 110 traits was performed in R using the Pearson correlation, followed with a Bonferroni correction for multiple tests. Hierarchical clustering of trait associations and principal component analyses were used to discern shared immune response and genetic relationships. The results demonstrate that G2 expression on naive blood NK cells was predictive of MCMV resistance. However, rapid G2(+) NK cell expansion following viral exposure occurred selectively in D(k) offspring; this response was more highly correlated with MCMV control than all other immune cell features. We infer that D(k)-licensed G2(+) NK cells efficiently detected missing-self MHC cues on viral targets, which elicited cellular expansion and target cell killing. Therefore, MHC polymorphism regulates licensing and detection of viral targets by distinct subsets of NK cells required in innate viral control.
    The Journal of Immunology 09/2013; 191(9). DOI:10.4049/jimmunol.1301388 · 4.92 Impact Factor
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