Disease relevance of Klra8

• Natural resistance to infection with mouse cytomegalovirus (MCMV) is controlled by a dominant locus, Cmv1 [1].
• Transgenic expression of the activating natural killer receptor Ly49H confers resistance to cytomegalovirus in genetically susceptible mice [1].
• Although there is a similar hierarchy of resistance to MCMV and HSV-1 with respect to the C57BL and BALB genetic backgrounds, the strain distribution pattern of HSV-1 replication in recombinant inbred mice suggests that Cmv-1 is not involved in restricting the spread of this virus [2].
• As these lack the Cmv1 gene, which provides a protective natural killer (NK) cell response in C57BL congenic mice, the C57BL background may carry a pancreatitis susceptibility gene able to counter NK-mediated restriction of viral replication [3].

High impact information on Klra8

• Susceptibility to infection with MCMV is controlled by Cmv1, a chromosome 6 locus that regulates natural killer (NK) cell activity against virally infected targets [4].
• 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 [4].
• TLR9-mediated cytokine secretion promotes viral clearance by NK cells that express the MCMV-specific receptor Ly49H [5].
• While some studies localized Cmv1 as distal to the Ly49 gene cluster, genetic and functional analysis identified Ly49h as a pivotal factor in resistance to MCMV [1].
• Our results are discussed in relation to recent reports demonstrating that innate resistance to MCMV requires the presence of NK cells expressing the KARAP/DAP12-associated receptor Ly49H [6].

Chemical compound and disease context of Klra8

• Effective natural killer (NK) cell recognition of murine cytomegalovirus (MCMV)-infected cells depends on binding of the Ly49H NK cell activation receptor to the m157 viral glycoprotein [7].

Biological context of Klra8

• For this, a total of 45 DNA markers corresponding to either cloned genes or microsatellites were mapped within a 7.9-cM interval overlapping the Cmv1 region [8].
• In our effort to clone Cmv1, we have constructed a high-resolution genetic linkage map in the proximity of the gene [8].
• To narrow the Cmv1 critical region, we developed novel NKC genetic markers and used these to genotype informative backcross and intra-NKC recombinant congenic mouse DNA samples [9].
• This high resolution, integrated physical and genetic NKC map will facilitate identification of Cmv1 and other NKC-linked loci that regulate NK cell-mediated immunity [9].
• The Cmv1 phenotypes of mice recombinant in this interval were tested by infection with MCMV [10].

Associations of Klra8 with chemical compounds

• In this regard, NKG2D and Ly49H lectin-like molecules trigger NK-cell functions recognizing, respectively class I-related stress-inducible molecules and the m157 murine CMV glycoprotein [11].
• In addition, we show that a second Ly49 family member that lacks an immunoreceptor tyrosine-based inhibitory motif and contains a charged residue in the transmembrane domain, Ly49H, also associates with DAP12 [12].

Other interactions of Klra8

• NKC species conservation suggests that the human NKC may contain orthologues for the mouse viral disease resistance genes, Cmv1 and Rmp1 [13].
• This result excludes Cd94 and Nkg2d as candidates whereas it localizes the Ly49 genes within the minimal genetic interval for Cmv1 [14].
• Two of these genes, Ly49h and i, are very closely related to the well characterized Ly49c gene in the carbohydrate recognition domain [15].
• In adult C57BL/6 mice, the control of MCMV in the spleen is mediated by a perforin-dependent mechanism, regulated in part by the Cmv-1 gene, which maps closely to the Ly49 family [16].
• Our recent genetic analysis of backcross mice demonstrated that the NK gene complex (NKC)-linked Cmv1 locus should reside between the Ly49 and Prp gene clusters on distal mouse chromosome 6 [9].

Analytical, diagnostic and therapeutic context of Klra8

• Using a site-directed mutagenesis approach, we have targeted residues conserved in receptors binding to m157 (Ly49H and Ly49I(129)) but different from receptors lacking m157 recognition (Ly49C, Ly49I(B6), and Ly49U) [17].
• To facilitate the cloning of the gene, we have created a high-resolution physical map of the Cmv1 genetic interval that is based on long-range restriction mapping by pulsed-field gel electrophoresis, fluorescence in situ hybridization analysis of interphase nuclei, and the assembly of a cloned contig [18].

References