When viruses jump from their natural host into human populations, one of the most pressing questions early in any subsequent epidemic is how the virus will evolve if it cannot be immediately contained and eradicated. In particular, if global pandemics result, or the disease becomes endemic in humans, will it become more or less harmful? Mathematical models of disease ecology and evolution show that when certain key phenotypic determinants of viral fitness are known, it is possible to predict the subsequent direction of virulence evolution. The problem is that these phenotypic details are hard to elucidate. In contrast, advances in molecular biology mean that when cross-species jumps do occur, a deluge of genomic data is generated, allowing genetic tracking of disease evolution. Do these genomic data allow us to predict much about future risk? In this proposal we seek to determine the molecular genetic basis of the evolution of the highly lethal myxoma virus after it was deliberately released as a biocontrol agent against rabbits in both Australia and Europe in the 1950s. These releases were inadvertent experiments in virus evolution, and even today myxoma virus is perhaps the best characterized case of virulence evolution in any vertebrate disease. Critically, the key phenotypic determinants of viral fitness are well characterized, so that the reason natural selection caused changes in myxoma virulence are extremely well known. But the genetic basis of the virulence evolution is not. We will use genomic analysis of viral isolates from both continents, including those sampled in the 1950s, to identify candidate genetic changes responsible for virulence evolution, and then engineer viruses with those mutations. The engineered lines will then be used to determine the causal role of the mutations in the virulence evolution. This work will generate a case study where we can link genotype to phenotype in a context where the transmission ecology is well enough known to predict evolution. Thus, we will be able to assess the power of genomic analysis for predicting future risk.

Public Health Relevance

Mathematical models suggest that when viruses like HIV or avian influenza jump into human populations, evolution in the subsequent epidemic(s) can make the disease more harmful or less harmful depending on the biological particulars. We will determine the genetic basis of changes in virulence which followed a uniquely well characterized species jump, and where the selective forces are well known. More generally, we aim to assess the value of genomic data in predicting public health risk.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Genetic Variation and Evolution Study Section (GVE)
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Challberg, Mark D
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Pennsylvania State University
Schools of Arts and Sciences
University Park
United States
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Kerr, Peter J; Cattadori, Isabella M; Rogers, Matthew B et al. (2017) Genomic and phenotypic characterization of myxoma virus from Great Britain reveals multiple evolutionary pathways distinct from those in Australia. PLoS Pathog 13:e1006252
Kerr, Peter J; Cattadori, Isabella M; Liu, June et al. (2017) Next step in the ongoing arms race between myxoma virus and wild rabbits in Australia is a novel disease phenotype. Proc Natl Acad Sci U S A 114:9397-9402
Liu, June; Cattadori, Isabella M; Sim, Derek G et al. (2017) Reverse Engineering Field Isolates of Myxoma Virus Demonstrates that Some Gene Disruptions or Losses of Function Do Not Explain Virulence Changes Observed in the Field. J Virol 91:
Eden, John-Sebastian; Read, Andrew J; Duckworth, Janine A et al. (2015) Resolving the Origin of Rabbit Hemorrhagic Disease Virus: Insights from an Investigation of the Viral Stocks Released in Australia. J Virol 89:12217-20
Eden, John-Sebastian; Kovaliski, John; Duckworth, Janine A et al. (2015) Comparative Phylodynamics of Rabbit Hemorrhagic Disease Virus in Australia and New Zealand. J Virol 89:9548-58
Di Giallonardo, Francesca; Holmes, Edward C (2015) Exploring Host-Pathogen Interactions through Biological Control. PLoS Pathog 11:e1004865
Kerr, Peter J; Liu, June; Cattadori, Isabella et al. (2015) Myxoma virus and the Leporipoxviruses: an evolutionary paradigm. Viruses 7:1020-61
Di Giallonardo, Francesca; Holmes, Edward C (2015) Viral biocontrol: grand experiments in disease emergence and evolution. Trends Microbiol 23:83-90
Kovaliski, John; Sinclair, Ron; Mutze, Greg et al. (2014) Molecular epidemiology of Rabbit Haemorrhagic Disease Virus in Australia: when one became many. Mol Ecol 23:408-20
Elsworth, Peter; Cooke, Brian D; Kovaliski, John et al. (2014) Increased virulence of rabbit haemorrhagic disease virus associated with genetic resistance in wild Australian rabbits (Oryctolagus cuniculus). Virology 464-465:415-423

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