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Experimental viral evolution to specific host MHC genotypes reveals fitness and virulence trade-offs in alternative MHC types.

ABSTRACT: The unprecedented genetic diversity found at vertebrate MHC (major histocompatibility complex) loci influences susceptibility to most infectious and autoimmune diseases. The evolutionary explanation for how these polymorphisms are maintained has been controversial. One leading explanation, antagonistic coevolution (also known as the Red Queen), postulates a never-ending molecular arms race where pathogens evolve to evade immune recognition by common MHC alleles, which in turn provides a selective advantage to hosts carrying rare MHC alleles. This cyclical process leads to negative frequency-dependent selection and promotes MHC diversity if two conditions are met: (i) pathogen adaptation must produce trade-offs that result in pathogen fitness being higher in familiar (i.e., host MHC genotype adapted to) vs. unfamiliar host MHC genotypes; and (ii) this adaptation must produce correlated patterns of virulence (i.e., disease severity). Here we test these fundamental assumptions using an experimental evolutionary approach (serial passage). We demonstrate rapid adaptation and virulence evolution of a mouse-specific retrovirus to its mammalian host across multiple MHC genotypes. Critically, this adaptive response results in trade-offs (i.e., antagonistic pleiotropy) between host MHC genotypes; both viral fitness and virulence is substantially higher in familiar versus unfamiliar MHC genotypes. These data are unique in experimentally confirming the requisite conditions of the antagonistic coevolution model of MHC evolution and providing quantification of fitness effects for pathogen and host. These data help explain the unprecedented diversity of MHC genes, including how disease-causing alleles are maintained.

SUBMITTER: Kubinak JL

PROVIDER: S-EPMC3295311 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Experimental viral evolution to specific host MHC genotypes reveals fitness and virulence trade-offs in alternative MHC types.

Kubinak Jason L JL Ruff James S JS Hyzer Cornelius Whitney CW Slev Patricia R PR Potts Wayne K WK

Proceedings of the National Academy of Sciences of the United States of America 20120207 9

The unprecedented genetic diversity found at vertebrate MHC (major histocompatibility complex) loci influences susceptibility to most infectious and autoimmune diseases. The evolutionary explanation for how these polymorphisms are maintained has been controversial. One leading explanation, antagonistic coevolution (also known as the Red Queen), postulates a never-ending molecular arms race where pathogens evolve to evade immune recognition by common MHC alleles, which in turn provides a selectiv ...[more]

PMID: 22323587

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Project description:The rapid emergence of phage-resistant bacterial mutants is a major challenge for phage therapy. Phage cocktails have been considered one approach to mitigate this issue. However, the synergistic effect of randomly selected phages in the cocktails is ambiguous. Here, we rationally designed a phage cocktail consisting of four phages that utilize the lipopolysaccharide (LPS) O antigen, the LPS outer core, the LPS inner core, and the outer membrane proteins BtuB and TolC on the Salmonella enterica serovar Enteritidis cell surface as receptors. We demonstrated that the four-phage cocktail could significantly delay the emergence of phage-resistant bacterial mutants compared to the single phage. To investigate the fitness costs associated with phage resistance, we characterized a total of 80 bacterial mutants resistant to a single phage or the four-phage cocktail. We observed that mutants resistant to the four-phage cocktail were more sensitive to several antibiotics than the single-phage-resistant mutants. In addition, all mutants resistant to the four-phage cocktail had significantly reduced virulence compared to wild-type strains. Our mouse model of Salmonella Enteritidis infection also indicated that the four-phage cocktail exhibited an enhanced therapeutic effect. Together, our work demonstrates an efficient strategy to design phage cocktails by combining phages with different bacterial receptors, which can steer the evolution of phage-resistant strains toward clinically exploitable phenotypes. IMPORTANCE The selection pressure of phage promotes bacterial mutation, which results in a fitness cost. Such fitness trade-offs are related to the host receptor of the phage; therefore, we can utilize knowledge of bacterial receptors used by phages as a criterion for designing phage cocktails. Here, we evaluated the efficacy of a phage cocktail made up of phages that target four different receptors on Salmonella Enteritidis through in vivo and in vitro experiments. Importantly, we found that pressure from phage cocktails with different receptors can drive phage-resistant bacterial mutants to evolve in a direction that entails more severe fitness costs, resulting in reduced virulence and increased susceptibility to antibiotics. These findings suggest that phage cocktail therapy using combinations of phages targeting different important receptors (e.g., LPS or the efflux pump AcrAB-TolC) on the host surface can steer the host bacteria toward more detrimental surface mutations than single-phage therapy, resulting in more favorable therapeutic outcomes.

Dataset Information

Experimental viral evolution to specific host MHC genotypes reveals fitness and virulence trade-offs in alternative MHC types.

Publications

Experimental viral evolution to specific host MHC genotypes reveals fitness and virulence trade-offs in alternative MHC types.

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