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Michael E. Grigg, Ph.D.
Building 4, Room B1-06
4 Memorial Drive
Bethesda, MD 20892-0425
Phone: 301-402-1609
Fax: 301-402-0079
griggm@niaid.nih.gov

Laboratory of Parasitic Diseases

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Michael E. Grigg, Ph.D.

Photo of Michael E. Grigg, Ph.D.

Chief, Molecular Parasitology Section, LPD

Major Areas of Research

  • Virulence shifts in protozoan parasites: biology and genetics
  • Forward/reverse genetics and functional genomic screens that identify protozoan virulence factors
  • Immunoparasitology and mechanisms of host resistance against protozoan parasites
  • Parasite gene families that modulate host immunity, infectivity, and parasite pathogenesis
 

Program Description

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.

Our research is focused on the phylogenetics and pathogenesis of several parasitic protozoa, including diplomonads (i.e., Giardia spp.), kinetoplastids (i.e., Leishmania spp.), and the apicomplexa (i.e., Toxoplasma gondii, Neospora spp., Sarcocsytis spp.). 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 using animal models of infection is identifying parasite surface and secreted effector molecules to determine their role in parasite pathogenesis and subversion of host immunity. Eliminating the ability of the parasite to evade sterilizing immunity is central to controlling both its propagation and its pathogenesis, as no vaccine or drug is currently capable of doing this. Despite its prevalence and importance as a human pathogen, surprisingly little is known about how Toxoplasma causes disease. Our research is contributing valuable insight into parasite-specific molecular strategies of eukaryotic pathogenesis. We have recently expanded our research effort to study Leishmania and Giardia in order 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:

  • 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
  • Pursuing functional genomic, genetic, and bioinformatic approaches to identify and characterize discrete virulence factors that contribute to protozoan 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
  • Determining changes in gene expression and pursuing structural and immunological analyses to investigate how parasite cell-surface antigens that regulate host immunity contribute to parasite infectivity
Because 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.

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Biography

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.

Research Group

Current

Photo of Beth Gregg, Ph.D.
Beth Gregg, Postdoctoral IRTA
Ph.D., Univ. of Pennsylvania, 2012
Support: NSF grant
Project: Identification of parasite factors impacting host innate immune signaling
Photo of Katie Haman
Katie Haman, IRTA/UBC Ph.D. Student
D.V.M., Univ. of Georgia, 2012
Support: UBC Fellowship
Project: Land-to-sea flow of protozoal pathogens
Photo of Stefano Iantorno, B.A.
Stefano Iantorno, OxCam Ph.D. Student
B.A., UC-Berkeley, 2010
Support: CIFAR grant
Project: Genetic exchange in Leishmania tropica
Photo of Andrea Kennard
Andrea Kennard, Hopkins Ph.D. Student
B.A., UC-Boulder, 2009
Support: NIAID
Project: Host range expansion in Toxoplasma gondii: utilizing forward genetics to map virulence loci
Photo of Asis Khan, Ph.D.
Asis Khan, Staff Scientist
Ph.D., Jadaypur, India, 2003
Support: NIAID
Project: Immunobiology and coevolution of host-parasite interactions: protozoan pathogens
Photo of Livia Martins
Livia Martins, Brazilian Ph.D. Student
M.Sc., UENF, Brazil, 2009
Support: CNPq Brazil
Project: Toxoplasma in blood donors from Brazil: parasite genotypes that associate with severe ocular toxoplasmosis
Photo of Viviana Pzsenny
Viviana Pzsenny, Contractor
Ph.D., Univ. of Buenos Aires, Argentina, 1994
Support: NIAID
Project: Toxoplasma surface antigens and immunity
Photo of Juan David Ramirez
Juan David Ramirez, Visiting Fellow - IRTA
Ph.D., Univ. de Los Andes, Columbia, 2012
Support: PEW Latin American Fellow
Project: Giardia and new world Leishmania phylogenomics and disease
Photo of Dionne Robinson
Dionne Robinson, Postdoctoral IRTA
Ph.D., Johns Hopkins, 2013
Support: INRO Fellow
Project: Sex and Endocrine effects modulating Toxoplasma pathogenesis
photo of Amy Sweeny
Amy Sweeny, Post-baccalaureate IRTA
B.A., Princeton, 2012
Support: GF-II grant
Project: Ecology and molecular characterization of protozoa infecting eastern Pacific wildlife populations
 

Alumni

Name

Position

Years at NIH

Current Position

Leila Shobab LSHTM M.Sc. Student 2006-07 Endocrinology Fellow, U Toronto
Spencer Magargal Post-baccalaureate IRTA 2007-08 Pediatric Resident, Virginia Commonwealth U
Sundar Natarajan Research Fellow 2007-13 Chief Veterinarian, Beltsville Clinic, MD
Chloe Gottlieb Visiting Fellow-IRTA 2008-10 Assistant Professor, U Ottawa
Erika Lamb IRTA 2008-10 Immunologist, Division of AIDS, NIAID
Robin Miller Post-baccalaureate IRTA 2008-10 Ph.D. Student, USUHS
James Wasmuth Visiting Fellow-IRTA 2008-10 Assitant Professor, U Calgary
Amanda Gibson Post-baccalaureate IRTA 2009-10 Ph.D. Student, U Indiana
Jered Wendte OSU M.Sc. Student 2009-11 Ph.D. Student, University of Indiana
Alessandra Commodaro Visiting Fellow-IRTA 2010-14 Assistant Professor, Sao Paulo University
Wendy Fujita Post-baccalaureate IRTA 2010-11 Medical Student, Emory
Alexandra Gast Post-baccalaureate IRTA 2010-11 Medical Student, Harvard
Gezahegn Gorfu Research Fellow 2010-13 Assistant Professor, Howard University
Mourad Barhoumi Visiting Fellow-IRTA 2011-13 Assistant Professor, Pasteur Institute at Tunis
Melissa Chiasson Post-baccalaureate IRTA 2011-13 Ph.D. Student, U Washington
Lorraine Thompson UC-Davis M.Sc. Student 2011-12 Veterinarian Resident, Marine Mammal Center
Leeanne Goodrich Post-baccalaureate IRTA 2012-13 Ph.D. Student, UC-San Francisco

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Selected Publications

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).

Visit PubMed for a complete publication listing.

Last Updated February 14, 2013