Identification of Quantitative Trait Loci for Susceptibility to Mouse Adenovirus Type 1

Abstract

Adenoviruses cause 5 to 10% of respiratory illnesses in children and are associated with acute pneumonia in children in developing countries, where the viruses are a major cause of illness and death (21). Five to 15% of pediatric bone marrow transplant patients develop adenovirus infections; morbidity ranges from 50 to 80% (8,9,12,16,27,38). However, very little is known about adenovirus pathogenesis, especially contributions of host factors to disease susceptibility. Mouse adenovirus type 1 (MAV-1) provides an excellent model for studying susceptibility to infectious disease because it can be studied in the natural host.Inbred strains of mice with different susceptibilities to MAV-1 infection have been identified previously (14,33). SJL/J mice are highly susceptible to MAV-1 infection, with a 50% lethal dose (LD 50 ) more than 4 log units lower than those for other strains of mice, including C3H/HeJ, BALB/cJ, 129/J, and C57BL/6J (33). In vivo studies with immunodeficient mice have demonstrated the importance of innate and adaptive immunity in response to MAV-1 infections. The presence of T cells contributes to immunopathology during the acute phase of infection and to clearance of virus in long-term infection (25). B cell-deficient mice are highly susceptible to MAV-1 infections and die very early, at 6 to 9 days postinfection (p.i.), of a disseminated infection (26). T cell-independent production of neutralizing antiviral immunoglobulin M is a critical factor for control of MAV-1 infection. Infection of primary cells of susceptible and resistant mice ex vivo gives equivalent yields of virus, and sublethal irradiation renders resistant mice susceptible (33). These results suggest that host immune response factors play a role in susceptibility to MAV-1.We have compared the adaptive immune responses that have been characterized as being important for control of MAV-1 infection (25, 26), as well as NK cell function and induction of cytokines and chemokines by infection, in susceptible and resistant mice (A. Welton and K. Spindler, unpublished data). To date, we have not identified physiological differences between susceptible and resistant strains have been identified by using these approaches. In this report, we show that MAV-1 susceptibility is linked to mouse chromosome 15 (Chr 15) and unlinked to the H-2 major histocompatibility locus. We used a genomewide search strategy, quantitative trait locus (QTL) detection, to identify host factors associated with susceptibility to MAV-1. This method is advantageous because it does not require prior hypotheses of the pathogenic mechanism and can therefore reveal novel pathways. We measured the susceptibility phenotypes of 192 backcross progeny. The analysis identified a major QTL on distal Chr 15 with a highly significant logarithm of odds (LOD) score of 21.2 and a minor QTL on Chr 5 with a suggestive LOD score of 1.2, based on 5,000 permutations of the mapping analysis. A LOD score of 21 means that the odds are 10 21 :1 in favor of linkage. The Chr 15 locus alone accou...

Recent advances in host–virus interactomics during entry and infection

“…39 Welton et al used a genome-wide search strategy, quantitative trait locus (QTL) detection, to identify host factors associated with susceptibility of congenic mouse to MAV-1. 40 The H-2 s haplotype of SJL/J mice was shown not to be associated with susceptibility to MAV-1, and the susceptibility of MAV-1-infected (BALB/cJ × SJL/J) F1 mice was intermediate between that of SJL/J and BALB/cJ mice, indicating that susceptibility is a genetically controlled quantitative trait. Through the analyses of 192 backcross progeny in a genome scan with polymorphic markers, a major QTL was detected on chromosome 15 (logarithm of odds [LOD] score of 21) and MAV-1 susceptibility was shown to be unlinked to the H-2 major histocompatibility locus.…”

“…Mice that differ in their inherent susceptibilities can be bred and the progenies can be subjected to linkage analyses to identify chromosomal location of candidate genes. Studies in this line have created low-resolution mapping of several mouse genes responsible for susceptibility/ resistance to mouse cytomegalovirus (MCMV; reviewed in Webb et al 38 ), West Nile virus 39 and mouse adenovirus type 1 (MAV-1 40 ). [38][39][40] The pattern of susceptibility/resistance to MCMV infection has identified the Cmv1 locus, a stimulatory member (Ly49H) of Ly49 receptor gene family (homolog of human KIR genes).…”

“…Studies in this line have created low-resolution mapping of several mouse genes responsible for susceptibility/ resistance to mouse cytomegalovirus (MCMV; reviewed in Webb et al 38 ), West Nile virus 39 and mouse adenovirus type 1 (MAV-1 40 ). [38][39][40] The pattern of susceptibility/resistance to MCMV infection has identified the Cmv1 locus, a stimulatory member (Ly49H) of Ly49 receptor gene family (homolog of human KIR genes). The importance of Cmv1/Ly49H in modulating MCMV infection in mouse has underlined the role of stimulatory KIRs in controlling viral infections through their interactions with major histocompatibility complex-I (MHC-I) molecules.…”

Evolutionary conservation of metabolism explains howDrosophila nutrigenomics can help us understand human nutrigenomics

“…In many mouse studies, the first approach has been used, whereby hundreds of F 2 mice are individually phenotyped and genotyped (Cheung et al, 2004;Devor et al, 2005;Kim et al, 2005;Kleeberger, 2005;Welton et al, 2005). For the second approach, Trudy Mackay's laboratory has developed a collection of Drosophila RI lines (Mackay, 2001) that our laboratory and others have used to identify obesity QTLs (Clark and Keith, 1988;De Luca et al, 2005).…”

Matrix Metalloproteinase Activity in Infections by an Encephalitic Virus, Mouse Adenovirus Type 1

“…We mapped a major quantitative trait locus (QTL) for susceptibility, Msq1, to the Ly6 locus on mouse chromosome (Chr) 15 in a backcross between susceptible SJL and resistant BALB/c mice (20,21). Some phenotypes that are related to encephalitis and BBB disruption are linked to Msq1, including high brain viral loads and disruption of the BBB (measured by permeability to small-molecule dyes) (22).…”