This K08 award will provide Dr. Adam Lauring with the necessary resources and protected time to achieve his objective of applying basic aspects of population genetics and quasispecies theory to explain the dynamics of RNA viruses in infected hosts. In so doing, he plans to bridge the gap between contemporary population-based models and clinical infectious diseases. The award will allow Dr. Lauring to accomplish the following career development goals: (1) Gain experience with animal models of infection. (2) Obtain a firm grounding in population genetics and evolutionary theory. (3) Acquire experience with microarray assays and lay a statistical foundation for future genomics studies of complex populations. (4) Develop a working knowledge of computer modeling of evolutionary systems. (5) Become an independent investigator. To achieve these goals, he has developed a comprehensive career development plan that includes didactic coursework, presentation at local and national research conferences, and ongoing input from a multidisciplinary advisory committee of experts in each training area. Because RNA viruses replicate with rapid kinetics and high mutation rates, they exist as a swarm of diverse variants that are genetically linked, interact cooperatively on a functional level, and together contribute to the characteristics of the population. Based on these considerations, virulence is hypothesized to be a population phenotype and determined by the structure, composition, and evolutionary capacity of the infecting population. A novel microarray platform is described, and will be applied to a well-defined in vivo model of infection in two specific aims.
(Aim 1) To characterize, at a functional level, the dynamics of an evolving viral population in vivo using poliovirus, an archetypal RNA virus. Experiments are outlined which address the impact of host bottlenecks on viral diversity and the balancing effect of viral mutation rate.
(Aim 2) To define evolutionary capacity as a property of the infecting population and its relationship to virulence and attenuation. A library of distinct viral populations will be screened for adaptive potential, and candidates that differ in their evolutionary capacity will be evaluated in pathogenesis and vaccine models.
RNA viruses cause a wide variety of diseases from AIDS to influenza and are of increasing concern as emerging pathogens and bioterror agents. Their unique evolutionary properties make them particularly challenging targets for vaccines and antiviral drugs. The population-based approach outlined here is broadly applicable to this group of pathogens and may lead to novel therapeutic and preventive strategies.
|Long, D; Deng, X; Singh, P et al. (2016) Identification of genetic variants associated with susceptibility to West Nile virus neuroinvasive disease. Genes Immun 17:298-304|
|Long, Dustin; Fix, Oren K; Deng, Xutao et al. (2014) Whole genome sequencing to identify host genetic risk factors for severe outcomes of hepatitis a virus infection. J Med Virol 86:1661-8|
|Venkatesan, A; Tunkel, A R; Bloch, K C et al. (2013) Case definitions, diagnostic algorithms, and priorities in encephalitis: consensus statement of the international encephalitis consortium. Clin Infect Dis 57:1114-28|
|Lauring, Adam S; Lee, Tzong-Hae; Martin, Jeffrey N et al. (2012) Lack of evidence for mtDNA as a biomarker of innate immune activation in HIV infection. PLoS One 7:e50486|
|Lauring, Adam S; Acevedo, Ashley; Cooper, Samantha B et al. (2012) Codon usage determines the mutational robustness, evolutionary capacity, and virulence of an RNA virus. Cell Host Microbe 12:623-32|
|Lauring, Adam S; Andino, Raul (2011) Exploring the fitness landscape of an RNA virus by using a universal barcode microarray. J Virol 85:3780-91|
|Lauring, Adam S; Jones, Jeremy O; Andino, Raul (2010) Rationalizing the development of live attenuated virus vaccines. Nat Biotechnol 28:573-9|
|Lauring, Adam S; Andino, Raul (2010) Quasispecies theory and the behavior of RNA viruses. PLoS Pathog 6:e1001005|
|Webster, Dale R; Hekele, Armin G; Lauring, Adam S et al. (2009) An enhanced single base extension technique for the analysis of complex viral populations. PLoS One 4:e7453|