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Experimental viral evolution reveals major histocompatibility complex polymorphisms as the primary host factors controlling pathogen adaptation and virulence

Genes & Immunity volume 14, pages 365–372 (2013)Cite this article

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Abstract

Using an experimental evolution approach, we recently demonstrated that the mouse-specific pathogen Friend virus (FV) complex adapted to specific major histocompatibility complex (MHC) genotypes, which resulted in fitness tradeoffs when viruses were exposed to hosts possessing novel MHC polymorphisms. Here we report the analysis of patterns of pathogen adaptation and virulence evolution from viruses adapting to one of three hosts that differ across the entire genome (A/WySn, DBA/2J and BALB/c). We found that serial passage of FV complex through these mouse genotypes resulted in significant increases in pathogen fitness (156-fold) and virulence (11-fold). Adaptive responses by post-passage viruses also resulted in host–genotype-specific patterns of adaptation. To evaluate the relative importance of MHC versus non-MHC polymorphisms as factors influencing pathogen adaptation and virulence, we compared the magnitude of fitness tradeoffs incurred by post-passage viruses when infecting hosts possessing either novel MHC polymorphisms alone or hosts possessing novel MHC and non-MHC polymorphisms. MHC polymorphisms alone accounted for 71% and 83% of the total observed reductions in viral fitness and virulence in unfamiliar host genotypes, respectively. Strikingly, these data suggest that genetic polymorphisms within the MHC, a gene region representing only ∼0.1% of the genome, are major host factors influencing pathogen adaptation and virulence evolution.

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Acknowledgements

This work was supported by National Science Foundation Grant DEB 0918969 (to WKP and Dr Fred Adler); National Science Foundation Doctoral Dissertation Improvement Grant DEB 0910052 (to JLK and WKP); and National Science Foundation Educational Outreach Grant DGE 08-41233 (to JLK and JSR). We thank Dr Sandra Ruscetti for her useful insights regarding FV complex as well as her generous provision of reagents throughout these experiments. We also thank Linda Morrison for her help in the design and optimization of assays. Finally, we thank two anonymous reviewers for their constructive comments during manuscript preparation.

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Authors and Affiliations

  1. Department of Biology, University of Utah, Salt Lake City, UT, USA

    J L Kubinak, J S Ruff, D H Cornwall, E A Middlebrook & W K Potts

  2. Department of Pathology, University of Utah, Salt Lake City, USA

    J L Kubinak

  3. Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, Hamilton, MT, USA

    K J Hasenkrug

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  1. J L Kubinak
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Correspondence to J L Kubinak.

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Kubinak, J., Ruff, J., Cornwall, D. et al. Experimental viral evolution reveals major histocompatibility complex polymorphisms as the primary host factors controlling pathogen adaptation and virulence. Genes Immun 14, 365–372 (2013). https://doi.org/10.1038/gene.2013.27

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