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E.M. Cantin, P. Lundberg, D. Gehman, C. Saris; Innate Resistance to Herpes simplex Virus is Genetically Complex . Invest. Ophthalmol. Vis. Sci. 2004;45(13):2258.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose:Recently, we identified the Herpes Resistance Locus (Hrl) on mouse chromosome 6 (c6). Resistant C57BL/6 (B6) and related strains express Hrlr while 129S6 (129) and most other strains express the susceptibility allele, Hrls. Additionally, we showed that augmented resistance of female mice was mediated by a second locus, the Sex Modifier Locus (Sml). The Hrl congenic strains p55–/–N5 (Hrls) and p55–/–N13 (Hrlr) and crosses between B6 and 129 strains were used for linkage analysis to refine the interval for Hrl and define Sml. Methods:Mice were inoculated on the right cornea with HSV–1 17+ at the 10xLD50 dose for 129S6 mice. Mice were monitored for mortality and animals exhibiting obvious symptoms of encephalitis were euthanized. 275 129x(B6.129)F1 N2 backcross mice were phenotyped and genotyped with 8 DNA markers spanning c6. 215 N2 mice judged to be a representative data set were selected for QTL analysis using MapManager QTXb17 (MMQTX); 60 mice with double crossover events and two or more marker failures were excluded. Results:The permutation test function of MMQTX generates a likelihood ratio statistic (LRS) as a measure of significance of the identified QTLs; Highly Significant was LRS = 10.8, Significant was LRS = 5.9 and Suggestive was LRS = 1.2. Two QTLs were observed; one at D6Mit61 adjacent to the TNF p55 receptor had a peak LRS of 3.5 and the other spanning D6Mit384–D6Mit284 had a LRS of 2.9–3.1. Setting D6Mit61 to background generated a separate Significant QTL ranging from D6Mit284 to D6Mit105 (peak LRS 6.4); this broad QTL spans the candidate region defined by the Hrl congenic p55–/– strains. Importantly, by looking for interacting QTL instead of individual QTL, strong interactions were observed for D6Mit69 and D6Mit55 that flank the Significant QTL; the LRS for the two markers is 22.6 and for their interaction is 20.1 which is Highly Significant. 129 and p55–/–N5 and B6 and p55–/–N13 are respectively, equally susceptible and resistant, and the (B6.129)F1 is resistant. Hence, it was surprising to find that the (p55–/–N5xp55–/–N13)F1 was susceptible. Analyses of further crosses provided definite evidence for involvement of TNF signaling in Hrl mediated resistance as suggested by the QTL analysis. Finally stratifying the phenotypic data by sex indicated that Sml displays "parent–of–origin" effects. Conclusions:Multiple genetic loci control resistance to mortality arising from HSV encephalitis, including Hrl and p55, which are linked loci on c6 and Sml whose location is unknown. Sex biased resistance to HSV mediated by Sml may involve genetic imprinting.
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