Michael E. Grigg, Ph.D.

Investigator

Description of Research Program

Parasitic protozoa are serious pathogens of humans and animals throughout the world whose biology is quite remarkable. Studies investigating their cell and molecular biology have identified unique paradigms of eukaryotic pathogenesis, including antigenic variation, virulence shifts and RNA editing. The primary goal of the Molecular Parasitology Unit is to understand the molecular basis of virulence and pathogenesis in a class of parasitic protozoa known as the Apicomplexa.

Our research is focused primarily on the food and water-borne parasite, Toxoplasma gondii, a serious pathogen capable of causing lethal infections in the developing fetus and in immunocompromised patients, as well as blinding chorioretinitis in both children and adults. In all hosts, Toxoplasma establishes long-term chronic infections that persist for life despite the induction of strong immunity. Eliminating the ability of the parasite to evade sterilizing immunity is central to controlling both its propagation and pathogenesis, as no vaccine or drug is currently capable of doing this. And despite its prevalence and importance as a human pathogen, surprisingly little is known about how Toxoplasma causes disease.

Our three-pronged research approach involves: (1) investigating the genetic basis of virulence shifts caused via sexual recombination in parasitic protozoa using Toxoplasma gondii as the genetic model; (2) determining the molecular interactions that control Toxoplasma pathogenesis in a naturally infectious, murine disease model; and (3) utilizing genomic and genetic tools to identify virulence factors essential for the ecological success of Apicomplexan pathogens from both a population and evolutionary vantage.

To conduct this research, our laboratory has developed a combination of new genetic, genomic, and molecular imaging techniques to identify parasite genes essential for entry into host cells, colonization, and subversion of host immunity in animal models of natural infection.

Current projects include the following:

• Investigating Toxoplasma outbreaks associated with unusually severe clinical disease to assess the contribution of sexual meioses in the evolution of new strains that possess altered biological potential
• Functional genomic, genetic, and bioinformatic approaches to identify and characterize discrete virulence factors that contribute to disease pathogenesis
• Bioimaging the host-pathogen interaction in vivo using real-time molecular imaging and in situ within anatomically intact host tissues to visualize host immune cells responding to parasite infected targets
• Gene expression, structural, and immunological analyses of parasite cell-surface antigens that regulate host immunity and contribute to parasite infectivity

Since relatively little is known about eukaryotic pathogenic processes as compared to the field of bacterial or viral pathogenesis, it is likely that entirely new mechanisms and principles of pathogenesis will emerge from our work.

Selected Recent Publications

M.E. Grigg. Population genetics, sex and the emergence of clonal lines of Toxoplasma gondii. In: “The Biology of Toxoplasma gondii” Ed. D. Soldati & J.W. Ajioka. 2007. Horizon Press

P.A. Conrad, M. Miller, C. Kreuder, E.R. James, J. Mazet, H. Dabritz, D.A. Jessup and M.E. Grigg. Sea otters as sentinels of Toxplasma gondii flow into the marine environment. Intl. J. Parasitol. 2005. 35:1155-68.

C.G. Jung*, C.Y-F. Lee*, and M.E. Grigg. The SRS superfamily of Toxoplasma gondii surface proteins. Intl. J. Parasitol. 2004. 34:285-296. *joint first-authors.

M.E. Grigg*, J-T. Kong*, L. Uyetake, S. Parmley and J.C. Boothroyd. Serotyping of Toxoplasma gondii infections in humans using synthetic peptides. J. Infect. Dis. 2003. 187:1484-1495.*joint first-authors

X-L. He, M.E. Grigg, J.C. Boothroyd, and K.C. Garcia. Structure of the immunodominant surface antigen from the Toxoplasma gondii SRS superfamily. Nature Struct. Biol. 2002. 9:606-611.

M.E. Grigg, S. Bonnefoy, A.B. Hehl, Y. Suzuki, and J.C. Boothroyd. Success and virulence in Toxoplasma as the result of sexual recombination between two distinct ancestries. Science 2001. 294:161-165.