All organisms are plagued by pathogens, which can rapidly evolve to overcome host defenses, resulting in increased host damage or mortality (virulence). Genetic variability of hosts provides one defense against this deadly potential. Experimental evolution of a murine retrovirus revealed 156-fold increases in fitness and 11-fold increases in virulence after just 10 serial passages through single-genotype hosts, but these dramatic increases were completely abolished when the virus faced five alternating host genotypes. Conditions that promote high transmission are also predicted to favor high virulence. For example, the virulence of Marek's disease virus of chickens has been steadily increasing over the past decades as barriers to transmission and host genetic diversity have been reduced. The long term objective of this study is to identify the mechanisms controlling virulence evolution of pathogens, which will lead to approaches for controlling the diseases emerging from such virulence increases. This study manipulates levels of both transmission and host genetic diversity during experimental viral evolution to quantify how each factor controls the evolution of pathogen transmissibility, replication and virulence (Aim 1). These experiments will be conducted in two hosts - mice (Mus) and chickens (Gallus), representing a model mammal and an avian agricultural species. For each host, two separate viral pathogens will be independently evaluated. We will utilize deep sequencing techniques to interrogate the entire genomes of the evolved viruses to identify the genetic basis of viral transmissibility, replication and virulence changes (Aim 2), which will fuel future experiments to discover specific mechanisms. These empirical data will form a basis for the development of mathematical models needed to deduce host consequences from pathogen replication and virulence evolution (Aim 3). The ability to study these processes experimentally and in real time provides a powerful yet under-utilized tool for dissecting the complex interactions between hosts and pathogens, which will be important for understanding and controlling pathogen-caused diseases.

Public Health Relevance

Beyond infectious disease itself, pathogens cause other diseases such as cancer, autoimmunity, and escape from vaccine immunity. This study identifies the causes of evolving pathogen virulence, which is fundamental to: 1) controlling pathogen-caused diseases, 2) controlling the emergence of new infectious diseases, 3) preparing against the use of pathogens as bioterrorism weapons and 4) controlling the global, antibiotic resistance crisis by minimizing the need for prophylactic antibiotics in domestic animals

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IDM-U (55))
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Eckstrand, Irene A
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University of Utah
Schools of Arts and Sciences
Salt Lake City
United States
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Ruff, James S; Saffarini, Raed B; Ramoz, Leda L et al. (2017) Mouse fitness measures reveal incomplete functional redundancy of Hox paralogous group 1 proteins. PLoS One 12:e0174975
Gaukler, Shannon M; Ruff, James S; Morrison, Linda C et al. (2016) Rofecoxib-Induced Deleterious Effects Escape Detection by Organismal Performance Assays. J Pharm Negat Results 7:4-11
Gaukler, Shannon Marie; Ruff, James Steven; Potts, Wayne K (2016) Paroxetine exposure skews litter sex ratios in mice suggesting a Trivers-Willard process. Behav Ecol 27:1113-1121
Gaukler, Shannon M; Ruff, James S; Galland, Tessa et al. (2016) Quantification of cerivastatin toxicity supports organismal performance assays as an effective tool during pharmaceutical safety assessment. Evol Appl 9:685-96
Ruff, James S; Hugentobler, Sara A; Suchy, Amanda K et al. (2015) Compared to sucrose, previous consumption of fructose and glucose monosaccharides reduces survival and fitness of female mice. J Nutr 145:434-41
Kubinak, Jason L; Cornwall, Douglas H; Hasenkrug, Kim J et al. (2015) Serial infection of diverse host (Mus) genotypes rapidly impedes pathogen fitness and virulence. Proc Biol Sci 282:20141568
Gaukler, Shannon M; Ruff, James S; Galland, Tessa et al. (2015) Low-dose paroxetine exposure causes lifetime declines in male mouse body weight, reproduction and competitive ability as measured by the novel organismal performance assay. Neurotoxicol Teratol 47:46-53
Nelson, A C; Cunningham, C B; Ruff, J S et al. (2015) Protein pheromone expression levels predict and respond to the formation of social dominance networks. J Evol Biol 28:1213-24
Ruff, James S; Saffarini, Raed B; Ramoz, Leda L et al. (2015) Fitness Assays Reveal Incomplete Functional Redundancy of the HoxA1 and HoxB1 Paralogs of Mice. Genetics 201:727-36
Kubinak, J L; Ruff, J S; Cornwall, D H et al. (2013) Experimental viral evolution reveals major histocompatibility complex polymorphisms as the primary host factors controlling pathogen adaptation and virulence. Genes Immun 14:365-72

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