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. 2002 Aug 20;99(17):11260-4.
doi: 10.1073/pnas.162006499. Epub 2002 Aug 12.

MHC heterozygosity confers a selective advantage against multiple-strain infections

Dustin J Penn  1 , Kristy Damjanovich, Wayne K Potts
Affiliations

MHC heterozygosity confers a selective advantage against multiple-strain infections

Dustin J Penn et al. Proc Natl Acad Sci U S A. .

Abstract

Genetic heterozygosity is thought to enhance resistance of hosts to infectious diseases, but few tests of this idea exist. In particular, heterozygosity at the MHC, the highly polymorphic loci that control immunological recognition of pathogens, is suspected to confer a selective advantage by enhancing resistance to infectious diseases (the "heterozygote advantage" hypothesis). To test this hypothesis, we released mice into large population enclosures and challenged them with multiple strains of Salmonella and one of Listeria. We found that during Salmonella infections with three avirulent strains, MHC heterozygotes had greater survival and weight than homozygotes (unlike sham controls), and they were more likely to clear chronic Salmonella infection than homozygotes. In laboratory experiments, we found that MHC heterozygosity enhanced the clearance of multiple-strain Salmonella infections. Yet, contrary to what is widely assumed, the benefits of heterozygosity were due to resistance being dominant rather than overdominant, i.e., heterozygotes were more resistant than the average of parental homozygotes, but they were not more resistant than both. The fact that MHC heterozygotes were more resistant to infection and had higher fitness than homozygotes provides a functional explanation for MHC-disassortative mating preferences.

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Figures

Fig 1.
Fig 1.
Kaplan–Meier plots showing the survivorship of all of the mice (a), experimentally infected mice (b), and sham-control mice (c) in the population enclosures. Arrows indicate the timing of infections: (arrow 1) Salmonella aroA (2 × 106 cfu per mouse), (arrow 2) Salmonella 628 (106 cfu per mouse), (3) Salmonella LT2 (8 × 105 cfu per mouse), (arrow 4) Salmonella aroA, 628, LT2, PMAC45, and PMAC51 (total 106 cfu per mouse), and (arrows 5 and 6) two infections of Listeria (106 cfu per mouse).
Fig 2.
Fig 2.
Health and reproduction of mice in the population enclosures. (a) Changes in body weight of males before the virulent epidemics (F2 segregants; infected, P = 0.015, n = 51; controls, P = 0.4, n = 48). (b) Reproduction of females in infected populations (P = 0.076, n = 60) (controls, P = 0.80, n = 64, data not shown). (c) Mice at the end of the experiment from the experimental populations that were still infected or completely cleared the Salmonella infection (P = 0.034, n = 58).
Fig 3.
Fig 3.
Resistance of mice to Salmonella in the laboratory. (a) Pathogen loads of mice infected with a single strain (628), either as a primary (P = 0.46, n = 29) or secondary challenge (P = 0.04, n = 30). Heterozygotes were not significantly more resistant than homozygotes in the primary (P = 0.44, n = 29, power = 0.09, least significant number = 348) or the secondary infections (P = 0.11, n = 30, power = 0.11, least significant number = 87). (b) Pathogen loads of mice infected with secondary challenge of a single or multiple strains. On average, heterozygotes were significantly more resistant than homozygotes to the multiple-strain infections (P = 0.011), but not the single-strain infection (P = 0.077). (c) Resistance of F2 segregant mice after a secondary challenge of multiple Salmonella strains. MHC genotype had a significant influence on pathogen load (Pdir = 0.0001, n = 27) and weight (P = 0.01). On average, MHC-heterozygous mice had lower pathogen loads (Pdir = 0.04) and lost less weight (Pdir = 0.02) during infection than homozygotes.
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