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Infection and Immunity, April 2003, p. 2079-2086, Vol. 71, No. 4
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.4.2079-2086.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Major Histocompatibility Complex Heterozygote Superiority during Coinfection

Erin E. McClelland, Dustin J. Penn,{dagger} and Wayne K. Potts*

Biology Department, University of Utah, Salt Lake City, Utah 84112

Received 22 July 2002/ Returned for modification 22 October 2002/ Accepted 18 December 2002

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.

* Corresponding author. Mailing address: Biology Department, University of Utah, 257 South 1400 East, Salt Lake City, UT 84112. Phone: (801) 585-9678. Fax: (801) 581-4668. E-mail: Potts{at}biology.utah.edu.

Editor: A. D. O'Brien

{dagger} Present address: Konrad Lorenz Institute, Austrian Academy of Sciences, A-1160 Vienna, Austria.

Infection and Immunity, April 2003, p. 2079-2086, Vol. 71, No. 4
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.4.2079-2086.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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