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 Section is to understand the molecular basis of virulence and pathogenesis in the parasitic protozoa.
My research program investigates the evolution, phylogenetics, and immunopathogenesis of prevalent zoonoses, specializing in protozoan parasites including the diplomonads (i.e., Giardia spp.), stremenopiles (i.e., Blastocystis spp.), amoebozoa (i.e., Entamoeba spp.), parabasalids (i.e., Trichomonas spp.), kinetoplastids (i.e., Leishmania spp., Trypanosoma spp.), and the apicomplexa (i.e., Toxoplasma gondii, Neospora spp., Sarcocsytis spp., Cryptosporidia spp.). We perform whole genome sequencing, population genetic, and molecular epidemiology analyses to identify protozoal agents associated with epidemic disease, and we use both forward and reverse genetics to identify genetic determinants governing virulence shifts among the parasitic protozoa. Our primary focus is Toxoplasma, a serious pathogen capable of causing lethal infections in the developing fetus, immunocompromised patients, and 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. Our work in Toxoplasma has identified parasite surface and secreted effector molecules that activate inflammasome pathways and dysregulate CD4 T-cell and B-cell activation. We also utilize pathogen-driven models of immune dysregulation to study the role of B-cell homing, regulatory T-cell function, and the gut microbiota in the regulation and maintenance of immune homeostasis in the context of inflammatory stimuli that contribute to or maintain the chronicity of intestinal inflammation. 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. Our research is contributing valuable insight into parasite-specific molecular strategies of eukaryotic pathogenesis. We have recently expanded our research effort to study Leishmania, Entamoeba, and Giardia to identify how other Category B pathogens have evolved to subvert host innate and adaptive immune responses to facilitate their survival, transmission, and success.
Current work in the Molecular Parasitology Section is divided into the following four projects: 1) To assess the contribution of sexual reproduction in the evolution of new, virulent strains of protozoan pathogens, we are investigating outbreaks associated with unusually severe clinical disease by sequencing Giardia, Leishmania, Toxoplasma, Sarcocystis, Neospora, and Cryptosporidia isolates in order to identify genetic determinants governing these “virulence shifts” in the parasitic protozoa; 2) To identify parasite genes essential for entry into host cells, colonization, and subversion of host immunity, we have developed a combination of functional genomic and genetic screens and molecular imaging techniques to determine the molecular interactions controlling Toxoplasma pathogenesis in a naturally infectious murine disease model; 3) To investigate how parasite surface antigens regulate host immunity and contribute to parasite infectivity, we are analyzing gene expression and performing structural, immunological, and gene knock-out analyses to disrupt parasite colonization and persistence; and 4) To discover proteins essential for completion of the Toxoplasma sexual cycle, we are generating sexual life cycle stage-specific transcriptome data (e.g.,merozoite, gametocyte, zygote) and using transgenic and reverse genetic strategies to identify bona fide targets for transmission blocking interventions and vaccine development.
Current projects include the following:
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Dr. Grigg earned his B.Sc. in 1989 from the University of British Columbia. He obtained his Ph.D. and D.I.C. in 1994 from the Imperial College of Science, Technology, and Medicine, University of London. From 1994 to 1997, Dr. Grigg was a Howard Hughes Medical Institute senior fellow at the University of Washington. From 1997 to 2001, he trained as a postdoctoral scholar in molecular parasitology at Stanford University. In 2002, he was appointed at the assistant professor level in medicine, microbiology, and immunology at the University of British Columbia. In 2006, he joined the Laboratory of Parasitic Disease as a tenure-track investigator. In 2013, he was appointed senior investigator at NIH. He is also an adjunct professor at the University of British Columbia and Oklahoma State University.
Cristina Carvalheiro, Visiting Fellow IRTAM.D., Ph.D., University of Sao Paulo, 2004Support: CNPqFellowProject: Congenital toxoplasmosis
Trent Gray, Post-baccalaureate IRTAB.Sc., Temple University, 2014Support: NIH AcademyProject: Targeted deletion of sexual stage-specific Toxoplasma SRS antigens
Patricia Sikorski, Ph.D. StudentM.Sc., Georgetown University, 2011Support: NIAIDProject: Role of complement in altering Toxoplasma pathogenesis
Ari Azani, Post-baccalaureate IRTAB.A., Brandeis University, 2015Support: INRO FellowProject: Population genetics of Leishmania and Entamoeba parasites
Members of the Molecular Parasitology Section, August 2015
Pediatric Resident, Virginia Commonwealth University
Chief Veterinarian, Beltsville Clinic, MD
Assistant Professor, University of Ottawa
Immunologist, Division of AIDS, NIAID
Ph.D. Student, USUHS
Assitant Professor, University of Calgary
Ph.D. Student, University of Indiana
OSU M.Sc. Student
Assistant Professor, Sao Paulo University
Medical Student, Emory University
Medical Student, Harvard University
Assistant Professor, Howard University
Assistant Professor, Pasteur Institute at Tunis
Ph.D. Student, University of Washington
UC-Davis M.Sc. Student
Veterinarian Resident, Marine Mammal Center
Ph.D. Student, UC-San Francisco
Ph.D. Student, UENF, Brazil
Ph.D. Student, Princeton University
Gorfu G, Cirelli KM, Melo MB, Mayer-Barber K, Crown D, Koller BH, Masters S, Sher A, Leppla SH, Moayeri M, Saeij JP, Grigg ME. Dual role for inflammasome sensors NLRP1 and NLRP3 in murine resistance to Toxoplasma gondii. MBio. 2014 Feb 18;5(1). pii: e01117-13.
Cirelli KM, Gorfu G, Hassan MA, Printz M, Crown D, Leppla SH, Grigg ME, Saeij JP, Moayeri M. Inflammasome sensor NLRP1 controls rat macrophage susceptibility to Toxoplasma gondii. PLoS Pathog. 2014 Mar 13;10(3):e1003927.
Song C, Chiasson MA, Nursimulu N, Hung SS, Wasmuth J, Grigg ME, Parkinson J. Metabolic reconstruction identifies strain-specific regulation of virulence in Toxoplasma gondii. Mol Syst Biol. 2013 Nov 19;9:708.
Shobab L, Pleyer U, Johnsen J, Metzner S, James ER, Torun N, Fay MP, Liesenfeld O, Grigg ME. Toxoplasma serotype is associated with development of ocular toxoplasmosis.J Infect Dis. 2013 Nov 1;208(9):1520-8.
Tonkin ML, Arredondo SA, Loveless BC, Serpa JJ, Makepeace KA, Sundar N, Petrotchenko EV, Miller LH, Grigg ME, Boulanger MJ. Structural and biochemical characterization of Plasmodium falciparum 12 (Pf12) reveals a unique interdomain organization and the potential for an antiparallel arrangement with Pf41. J Biol Chem. 2013 May 3;288(18):12805-17.
Wasmuth JD, Pszenny V, Haile S, Jansen EM, Gast AT, Sher A, Boyle JP, Boulanger MJ, Parkinson J, Grigg ME. Integrated bioinformatic and targeted deletion analyses of the SRS gene superfamily identify SRS29C as a negative regulator of Toxoplasma virulence. MBio. 2012 Nov 13;3(6).
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Last Updated August 18, 2015