Molecular Parasitology Section
Michael Grigg, Ph.D.
Chief, Molecular Parasitology Section
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.
Ph.D., 1994, Imperial College of Science, Technology, and Medicine, University of London
B.Sc., 1989, University of British Columbia
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.
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.