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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.

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:

  • Investigating protozoan 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: NIAID
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 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, Colombia, 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
photo of Cristina Carvalheiro

Cristina Carvalheiro, Visiting Fellow IRTA
M.D., Ph.D., University of Sao Paolo, 2004
Support: CNPqFellow
Project: Congenital toxoplasmosis

photo of Trent Gray

Trent Gray, Post-baccalaureate IRTA
B.Sc., Temple University, 2014
Support: NIH Academy
Project: Targeted deletion of sexual stage-specific Toxoplasma SRS antigens

photo of Patricia Sikorski

Patricia Sikorski, Ph.D. Student
M.Sc., Georgetown University, 2011
Support: NIAID
Project: Role of complement in altering Toxoplasma pathogenesis

 
photo of Ari Azani

Ari Azani, Post-baccalaureate IRTA
B.A., Brandeis University, 2015
Support: INRO Fellow
Project: Population genetics of Leishmania and Entamoeba parasites

 
photo of group members

Members of the Molecular Parasitology Section, August 2015

Alumni

Name

Position

Years at NIH

Current Position

Spencer Magargal

Post-baccalaureate IRTA

2007-08

Pediatric Resident, Virginia Commonwealth University

Sundar Natarajan

Research Fellow

2007-13

Chief Veterinarian, Beltsville Clinic, MD

Chloe Gottlieb

Visiting Fellow-IRTA

2008-10

Assistant Professor, University of 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, University of Calgary

Amanda Gibson

Post-baccalaureate IRTA

2009-10

Ph.D. Student, University of 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 University

Alexandra Gast

Post-baccalaureate IRTA

2010-11

Medical Student, Harvard University

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, University of 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

Livia Martins

Visiting Fellow-IRTA

2013-14

Ph.D. Student, UENF, Brazil

Malavika Rajeev

Post-baccalaureate IRTA

2014-15

Ph.D. Student, Princeton University

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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 August 18, 2015