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
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, RNA editing, and inactivation of host immune signaling networks to promote infection competency. 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 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. The expansion of our research focus to study Leishmania, Entamoeba, Trichomonas, and Giardia is largely the result of our continuing effort 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, andCryptosporidia isolates in order to identify genetic determinants governing “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 protozoan parasite pathogenesis in naturally infectious murine disease models; 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 fidetargets for transmission blocking interventions and vaccine development.
Our major 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.
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.
Beth Gregg, Postdoctoral IRTA
Ph.D., Univ. of Pennsylvania, 2012
Project: Identification of parasite factors impacting host innate immune signaling
Andrea Kennard, Hopkins Ph.D. Student
B.A., UC-Boulder, 2009
Project: Host range expansion inToxoplasma gondii: utilizing forward genetics to map virulence loci
Asis Khan, Staff Scientist
Ph.D., Jadaypur, India, 2003
Project: Immunobiology and coevolution of host-parasite interactions: protozoan pathogens
Viviana Pzsenny, Contractor
Ph.D., Univ. of Buenos Aires, Argentina, 1994
Project: Toxoplasma surface antigens and immunity
Juan David Ramirez, Visiting Fellow - IRTA
Ph.D., Univ. de Los Andes, Colombia, 2012
Support: PEW Latin American Fellow
Project: Giardia and new worldLeishmania phylogenomics and disease
Dionne Robinson, Postdoctoral IRTA
Ph.D., Johns Hopkins, 2013
Support: INRO Fellow
Project: Sex and Endocrine effects modulating Toxoplasmapathogenesis
Cristina Carvalheiro, Visiting Fellow IRTA
M.D., Ph.D., University of Sao Paulo, 2004
Project: Congenital toxoplasmosis
Trent Gray, Post-baccalaureate IRTA
B.Sc., Temple University, 2014
Support: NIH Academy
Project: Targeted deletion of sexual stage-specific Toxoplasma SRS antigens
Patricia Sikorski, Ph.D. Student
M.Sc., Georgetown University, 2011
Project: Role of complement in altering Toxoplasma pathogenesis
Ari Azani, Post-baccalaureate IRTA
B.A., Brandeis University, 2015
Support: INRO Fellow
Project: Population genetics ofLeishmania and Entamoebaparasites
|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|
|Stefano Iantorno||OxCam Ph.D. Student||2011-15||Medical Student, Columbia Univ|
|Katie Haman||IRTA/UBC Ph.D.||2012-16||Fish and Wildlife Veterinarian, WA|
|Amy Sweeny||Post-Bac IRTA||2013-15||Ph.D Student, Edinburgh University|
Lorenzi H, Khan A, Behnke MS, Namasivayam S, Swapna LS, Hadjithomas M, Karamycheva S, Pinney D, Brunk BP, Ajioka JW, Ajzenberg D, Boothroyd JC, Boyle JP, Dardé ML, Diaz-Miranda MA, Dubey JP, Fritz HM, Gennari SM, Gregory BD, Kim K, Saeij JP, Su C, White MW, Zhu XQ, Howe DK, Rosenthal BM, Grigg ME, Parkinson J, Liu L, Kissinger JC, Roos DS, David Sibley L.Local admixture of amplified and diversified secreted pathogenesis determinants shapes mosaic Toxoplasma gondii genomes. Nat Commun. 2016 Jan 7;7:10147.
Commodaro AG, Chiasson M, Sundar N, Rizzo LV, Belfort R Jr, Grigg ME. Elevated Toxoplasma gondii Infection Rates for Retinas from Eye Banks, Southern Brazil. Emerg Infect Dis. 2016 Apr;22(4):691-3.
Hutson SL, Wheeler KM, McLone D, Frim D, Penn R, Swisher CN, Heydemann PT, Boyer KM, Noble AG, Rabiah P, Withers S, Montoya JG, Wroblewski K, Karrison T, Grigg ME, McLeod R. Patterns of Hydrocephalus Caused by Congenital Toxoplasma gondii Infection Associate With Parasite Genetics. Clin Infect Dis. 2015 Dec 15;61(12):1831-4.
Blazejewski T, Nursimulu N, Pszenny V, Dangoudoubiyam S, Namasivayam S, Chiasson MA, Chessman K, Tonkin M, Swapna LS, Hung SS, Bridgers J, Ricklefs SM, Boulanger MJ, Dubey JP, Porcella SF, Kissinger JC, Howe DK, Grigg ME*, Parkinson J.*Systems-based analysis of the Sarcocystis neurona genome identifies pathways that contribute to a heteroxenous life cycle. MBio. 2015 Feb 10;6(1).
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).
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.