Major histocompatibility complex heterozygote superiority during coinfection

Abstract

Genes of the major histocompatibility complex (MHC) play a critical role in immune recognition, and many alleles confer susceptibility to infectious and autoimmune diseases. How these deleterious alleles persist in populations is controversial. One hypothesis postulates that MHC heterozygote superiority emerges over multiple infections because MHC-mediated resistance is generally dominant and many allele-specific susceptibilities to pathogens will be masked by the resistant allele in heterozygotes. We tested this hypothesis by using experimental coinfections with Salmonella enterica (serovar Typhimurium C5TS) and Theiler's murine encephalomyelitis virus (TMEV) in MHC-congenic mouse strains where one haplotype was resistant to Salmonella and the other was resistant to TMEV. MHC heterozygotes were superior to both homozygotes in 7 out of 8 comparisons (P = 0.0024), and the mean standardized pathogen load of heterozygotes was reduced by 41% over that of homozygotes (P = 0.01). In contrast, no heterozygote superiority was observed when the MHC haplotype combinations had similar susceptibility profiles to the two pathogens. This is the first experimental evidence for MHC heterozygote superiority against multiple pathogens, a mechanism that would contribute to the evolution of MHC diversity and explain the persistence of alleles conferring susceptibility to disease.

FIG. 1.

Hypothetical MHC-associated pathogen loads for three pathogens and the predicted combined pathogen loads during different dual infections. MHC genotypes infected with single pathogens (a, b, and c) show different patterns of susceptibility. Combined pathogen loads during dual infections (d and e) are obtained by adding the single pathogen loads for each genotype and standardizing the axes. When animals are infected with two pathogens that show opposite susceptibility profiles (a and b), heterozygotes are predicted to be superior (d). When animals are infected with two pathogens that show similar susceptibility profiles (a and c), heterozygotes are predicted to be intermediate (e). MHC-mediated resistance is dominant in all cases and is required for the predicted patterns (2).

FIG. 2.

Salmonella and TMEV loads for single infections. Pathogen loads of female (a) and male (c) animals of different MHC heterozygote combinations showing opposite susceptibility profiles. Pathogen loads of female (b) and male (d) animals of different MHC heterozygote combinations showing similar susceptibility profiles. In the case of opposite susceptibility profiles (a and c), all homozygotes were significantly different (P < 0.05 by t test), except the following: Salmonella loads for the d/d and q/q genotypic combinations in females (P = 0.08), TMEV loads for the d/d and k/k genotypic combinations in females (P = 0.17), and TMEV loads for the d/d and k/k genotypic combinations in males (P = 0.08). Sample sizes are indicated above each bar. spcd, spinal cord.

FIG. 3.

Salmonella and TMEV loads for coinfected mice of either opposite or similar susceptibility profiles. Pathogen loads are given for coinfected female (a) and male (c) animals of different MHC heterozygote combinations showing opposite susceptibility profiles. Pathogen loads are given for coinfected female (b) and male (d) animals of different MHC heterozygote combinations showing similar susceptibility profiles. In the case of opposite susceptibility profiles (a and c), all homozygotes were significantly different (P < 0.05 by t test), except TMEV loads for the b/b and q/q genotypic combinations in males (P = 0.07), and resistance was dominant (pathogen loads of heterozygotes were more like the resistant than the susceptible homozygote). In the case of similar susceptibility profiles, all homozygotes were significantly different (P < 0.05 by t test) for the Salmonella infection but not for the TMEV infection (P > 0.60). Sample sizes are indicated above each bar.

FIG. 4.

Standardized combined pathogen loads for animals showing opposite susceptibility profiles. We calculated the combined pathogen load from the individual Salmonella and TMEV loads for the two different genotypic combinations showing opposite susceptibility profiles, b/q (a, c, e, and g) and d/q (b, d, f, and h). This was done for two independent experiments and for each sex. Sample sizes are indicated above each bar.

FIG. 5.

Pooled standardized combined pathogen loads for genotypic combinations showing opposite (a and b) and similar (c) susceptibility profiles. The sexes and both experiments were pooled for the b/q and d/q combinations (a and b). All P values shown are from a Wilcoxon rank-sum test. Sample sizes are indicated above each bar.