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The combination of major histocompatibility complex (MHC) and non-MHC genes influences murine lymphocytic
Y L Eyler1, C J Pfau, K S Broomhall
1Department of Biology, Rensselaer Polytechnic Institute, Troy, New York 12180.
Abstract:
Resistance to the acute lethal disease caused by the docile strain of lymphocytic choriomeningitis (LCM) virus varies widely between different mouse strains. In order to study the inheritance of host influence on susceptibility to this strain of LCM virus, we crossed the F1 to the parent with the recessive disease phenotype. In all cases, susceptibility was dominant. In backcross progeny obtained from matings of parental strains differing in both major histocompatibility complex (MHC) and non-MHC (SWR; C3H), 90% of the challenged mice died, indicating that at least three loci controlled susceptibility to the disease. When the parental strains carried similar MHC haplotypes but dissimilar background genes (B10.BR; CBA), 78% of the backcross mice succumbed, indicating that at least two non-MHC loci influenced disease susceptibility. It is unlikely, however, that the same two non-MHC loci are critical in all genetic combinations, since F1 produced from two H-2 identical, resistant strains (B10.BR; C3H) were found to be fully susceptible. When congenic mice, differing only in the D-end of the MHC region, were analysed, 50% of the backcross animals died, indicating that one gene in the MHC region was important; segregation analysis comparing MHC serotype and disease outcome indicated the H-2D locus itself as the determining factor.
Insights
Mouse strain genetics significantly influence susceptibility to lymphocytic choriomeningitis (LCM) virus. Host genetic factors, including the major histocompatibility complex (MHC), control LCM virus disease outcome.
Area of Science:
- Immunology
- Genetics
- Virology
Background:
- Lymphocytic choriomeningitis (LCM) virus causes an acute lethal disease with variable severity in different mouse strains.
- Host genetic factors play a crucial role in determining susceptibility and resistance to LCM virus infection.
Purpose of the Study:
- To investigate the inheritance patterns of host genetic control over susceptibility to a docile strain of LCM virus.
- To identify specific genetic loci, including those within the major histocompatibility complex (MHC), that influence LCM virus disease outcome.
Main Methods:
- Cross-breeding experiments involving susceptible and resistant mouse strains.
- Analysis of backcross progeny to determine the mode of inheritance and identify contributing loci.
- Segregation analysis correlating MHC serotype with disease outcome in congenic mouse lines.
Main Results:
- Susceptibility to LCM virus was found to be dominant.
- At least three genetic loci control susceptibility when parental strains differ in both MHC and non-MHC genes.
- At least two non-MHC loci influence susceptibility when parental strains share MHC haplotypes.
- A single gene within the MHC, specifically the H-2D locus, was identified as a critical determinant of LCM virus disease outcome.
Conclusions:
- Host genetic background profoundly impacts LCM virus pathogenesis.
- The H-2D locus within the major histocompatibility complex is a key determinant of LCM virus susceptibility.
- Multiple non-MHC genes also contribute to the complex genetic control of LCM virus disease.