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

Scalzo, Anthony A.; Wheat, Roy; Dubbelde, Chad; Stone, Laurie R.; Clark, Patricia; Du, Ying; Dong, Naomi; Stoll, Janis; Yokoyama, Wayne M.; Brown, Michael G.

doi:10.1007/s00251-003-0591-8

Cited by 17 publications

(10 citation statements)

References 34 publications

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“…Mice with intra-region recombinations were confirmed and further backcrossed to the C57L or MA/My genetic background, followed by more extensive genetic analysis to pinpoint chromosome crossovers as we have described previously (13). The novel recombinant lines have been maintained at the University of Virginia in accordance with IACUC guidelines.…”

Section: Methodsmentioning

confidence: 99%

MHC Class I Dk Locus and Ly49G2+ NK Cells Confer H-2k Resistance to Murine Cytomegalovirus

Xie

Stadnisky

Brown

2009

The Journal of Immunology

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During virus infection, NK cells are needed in the body to provide early immune defense. Their activity is regulated by MHC class I-binding cell surface inhibitory and stimulatory receptors that include mouse Ly49, human killer Igrelated receptor (KIR), 3 and NKG2/CD94 receptors (1-3). NK cell-mediated virus control is subject to genetic factors that can influence viral replication and host mortality (4). For instance, the Ly49H activation receptor displayed on the surface of NK cells in C57BL/6 mice binds murine CMV (MCMV) m157 ligands at the surface of infected cells to impart MCMV resistance (5, 6). In New Zealand White, MA/My, and PWK strains, MCMV resistance also requires NK-mediated virus control, but Ly49H-independent defense mechanisms are key (7-11). It remains unclear which genetic factors are at work and how such factors mediate virus resistance through NK cells.Attempts have been made to identify genetic factors that underlie MCMV resistance/susceptibility traits in the offspring of genetic crosses between MCMV-resistant (Cmv r ) MA/My mice and strains that appear to be more MCMV susceptible (Cmv s ). To date, major MCMV control loci have been mapped to the MHC and NK gene complex (NKC) on chromosomes 17 and 6, respectively (9, 10). We have further shown that MHC polymorphism is respon- Materials and Methods Animalsmice were bred and maintained in a specificpathogen-free vivarium at the University of Virginia (Charlottesville, VA), which is fully certified by the American Association for Accreditation of Laboratory Animal Care. All recombinant congenic strains generated and used in this study were backcrossed to the progenitor strain C57L for at least 10 generations. All animal studies were approved by and conducted in accordance with the Institutional Animal Care and Use Committee (IACUC) of the University of Virginia. Recombinant congenic strain generation, genetic markers, and genotyping (C57L.M-H2k ϫ C57L)F 1 or (MA/My.L-H2 b ϫ MA/My)F 1 were brother ϫ sister mated and screened for recombination crossovers within the D17Mit16-D17Uva09 interval using several simple sequence-length polymorphism (SSLP) markers to distinguish MA/My and C57L alleles (Table I). SSLP-amplified PCR products were resolved in POP7-filled capillaries and analyzed on a Genetic Analyzer 3130xl using Data Collection (version 3.0) and GeneMapper software (version 4.0; Applied Biosystems) as described previously (10). Some unlabeled SSLP amplicons were fractionated in 4% agarose gel electrophoresis and visualized on an UV transilluminator after ethidium bromide staining.For generation of novel SSLP markers, chromosome 17 sequence data available from the National Center for Biotechnology Information were manually inspected for microsatellite repeat sequences. Sequence-specific

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Section: Methodsmentioning

confidence: 99%

MHC Class I Dk Locus and Ly49G2+ NK Cells Confer H-2k Resistance to Murine Cytomegalovirus

Xie

Stadnisky

Brown

2009

The Journal of Immunology

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“…The NKC is located on the distal arm of mouse chromosome 6. The segment Cd69 through D6Mit 13, represented in this figure, was constructed from data in http://www.informatics.jax.org along with phenotypic/genotypic data from parental and recombinant mice 39 , 54 , 55 , 56 …”

Section: Mendelian Analysis Of Restricted Viral Spread In the Brain Amentioning

confidence: 99%

A NK complex‐linked locus restricts the spread of herpes simplex virus type 1 in the brains of C57BL/6 mice

et al. 2015

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The most frequent cause of sporadic viral encephalitis in western countries is Herpes simplex virus (HSV). Despite treatment, mortality rates reach 20-30% while survivors often suffer from significant morbidity. In mice, resistance to lethal Herpes simplex encephalitis (HSE) is multifactorial and influenced by mouse and virus strain as well as route of infection. The ability to restrict viral spread in the brain is one factor contributing to resistance. After infection of the oral mucosa with HSV type 1 (HSV-1), virus spreads throughout the brains of susceptible strains but is restricted in resistant C57BL/6 mice. To further investigate restriction of viral spread in the brain, mendelian analysis was combined with studies of congenic, intra-natural killer complex (intra-NKC) recombinant and antibody-depleted mice. Results from mendelian analysis support the restriction of viral spread as a dominant trait and consistent with a single gene effect. In congenic mice, the locus maps to the NKC on chromosome 6 and is provisionally termed Herpes Resistance Locus 2 (Hrl2). In intra-NKC recombinants, the locus is further mapped to the segment Cd69 through D6Wum34; a different location from previously identified loci (Hrl and Rhs1) also associated with HSV-1 infection. Studies with antibody-depleted mice indicate the effect of this locus is mediated by NK1.1(+) expressing cells. This model increases our knowledge of lethal HSE, which may lead to new treatment options.

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“…MA/My and C57L breeder pairs were purchased from The Jackson Laboratory (Bar Harbor, ME) and housed in the MR-5 specific-pathogen-free vivarium at the University of Virginia, which is fully accredited by the American Association for Accreditation of Laboratory Animal Care. A simple sequence length polymorphism (SSLP) marker-assisted genome selection method was used to produce MA/My.L-H2 b (M.L-H2 b ) mice as we have described previously (11,30,33). Briefly, (C57L ϫ MA/My)F 1 hybrid mice were first backcrossed to MA/My.…”

Section: Methodsmentioning

confidence: 99%

Deficient Major Histocompatibility Complex-Linked Innate Murine Cytomegalovirus Immunity in MA/My.L-H2^bMice and Viral Downregulation of H-2^kClass I Proteins

Xie

Dighe²,

Clark³

et al. 2007

J Virol

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NK cells are key effectors of innate immunity and host survival during cytomegalovirus (CMV) infection. Innate murine CMV (MCMV) resistance in MA/My mice requires Ly49H/m157-independent H-2k-linked NK cell control. Here we show that replacement of MA/My H-2k with C57L H-2b susceptibility genes led to a remarkable loss of innate virus immunity, though NK gamma interferon was induced in H-2b and H-2k strains shortly after infection. Thus, H-2b genes expressed in C57L or MA/My.L-H2b are sufficient in alerting NK cells to intrusion but fail to support NK restraint of viral infection. In addition, novel H-2 recombinant strains were produced and utilized in a further refinement of a critical genetic interval controlling innate H-2k-linked MCMV resistance. Importantly, this analysis excluded the gene interval from Kk class I through class II. The responsible gene(s) therefore resides in an interval spanning Dk class Ia and more-distal major histocompatibility complex (MHC) nonclassical class Ib genes. Recently, the NK activation receptor Ly49P and MHC class I Dk proteins were genetically implicated in MCMV resistance, in part because Ly49P-expressing reporter T cells could specifically bind Dk molecules on MCMV-infected mouse embryonic fibroblasts (MEFs). However, as we found that H-2k innate resistance differs in the C57L or MA/My backgrounds and because MCMV very efficiently downregulates H-2k class I proteins in L929 cells and primary MEFs shortly after infection, a Ly49P/Dk model should not fully explain H-2k-linked MCMV resistance.

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

Cited by 17 publications

References 34 publications

MHC Class I Dk Locus and Ly49G2+ NK Cells Confer H-2k Resistance to Murine Cytomegalovirus

MHC Class I Dk Locus and Ly49G2+ NK Cells Confer H-2k Resistance to Murine Cytomegalovirus

A NK complex‐linked locus restricts the spread of herpes simplex virus type 1 in the brains of C57BL/6 mice

Deficient Major Histocompatibility Complex-Linked Innate Murine Cytomegalovirus Immunity in MA/My.L-H2^bMice and Viral Downregulation of H-2^kClass I Proteins

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

Cited by 17 publications

References 34 publications

MHC Class I Dk Locus and Ly49G2+ NK Cells Confer H-2k Resistance to Murine Cytomegalovirus

MHC Class I Dk Locus and Ly49G2+ NK Cells Confer H-2k Resistance to Murine Cytomegalovirus

A NK complex‐linked locus restricts the spread of herpes simplex virus type 1 in the brains of C57BL/6 mice

Deficient Major Histocompatibility Complex-Linked Innate Murine Cytomegalovirus Immunity in MA/My.L-H2bMice and Viral Downregulation of H-2kClass I Proteins

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Deficient Major Histocompatibility Complex-Linked Innate Murine Cytomegalovirus Immunity in MA/My.L-H2^bMice and Viral Downregulation of H-2^kClass I Proteins