Assistant Professor, Institute of Parasitology
T: 514 398 8764 | igor.cestari [at] mcgill.ca (Email) | Parasitology Building, P-212 | Website
BSc (Federal University of Pernambuco)
MSc, PhD (Oswaldo Cruz Institute – Fiocruz)
Dr. Cestari has a background in molecular and systems biology. He obtained his BS degree in biology with a specialty in genetics and MSc and Ph.D. degrees in molecular and cellular biology, studying the mechanisms of complement system evasion by trypanosomes. During his postdoc at the Center for Infectious Disease Research (Seattle, USA), he investigated the molecular mechanisms underlying the control of antigenic variation in trypanosomes, focusing on phosphoinositide signalling and transcriptional control and explored these processes for drug development. In 2018, he joined the Institute of Parasitology at McGill University. His laboratory focuses on the signalling and transcriptional control mechanisms that govern antigenic variation and drugs and vaccine development.
Signaling and transcriptional control mechanisms that govern antigenic variation. Development of new therapeutics, including drugs and vaccines.
Our laboratory is interested in the molecular mechanisms by which pathogens evade the host immune system to establish infection. We focus on Kinetoplastids, which include three main pathogens of medical importance: T. brucei, which causes Sleeping sickness in Africa; T. cruzi, which causes Chagas disease in the Americas; and Leishmania sp., which cause leishmaniasis in tropical and subtropical regions. Together, these parasites affect over 2 million people annually worldwide, especially in developing countries. While a few drugs are available for treating these diseases, they have limited efficacy, are highly toxic, and drug resistance is spreading. Hence, there is an urgent need to understand these organisms' biology for advancing disease control strategies. We have two main research programs:
1) Phosphoinositide signalling and regulation of antigenic variation: We are interested in the mechanisms that control the expression of genes encoding surface antigens known as variant surface glycoproteins (VSGs), which are essential for host immune evasion in the protozoan pathogen T. brucei. This parasite has over 2,500 VSG genes and pseudogenes but only expresses one VSG gene at a time from subtelomeric expression sites. T. brucei periodically change the VSG gene expressed by transcriptional switching or recombination mechanisms. This process results in the change of the surface antigen coat, which helps the parasite to escape host antibody recognition and clearance during infection. We discovered that phosphoinositide signalling plays a role in VSG expression and switching (Cestari and Stuart, 2015, PNAS). Our laboratory focuses on dissecting the signal transduction system that controls VSG monogenic expression and switching. We also identified a Telomeric Expression Site protein Complex (TESC) (Cestari et al. 2019, Mol Cell Biol) that functions in the control of telomeric chromatin organization, silencing and transcription of VSG genes. We are studying the TESC protein composition and topology, its role in regulating ES chromatin structure, and its function in maintaining silent and active telomeric VSG genes.
2) Vaccines and drugs for Chagas disease: There are limited preventive or therapeutic vaccines for diseases caused by protozoan pathogens. The parasite T. cruzi causes a chronic and lethal illness that affects millions of people. The Chagas disease develops over decades, often as a debilitating cardiac or gastrointestinal disease. There are no drugs that cure chronic Chagas disease, and no vaccines are available. Hence, there is an urgent need to develop new drugs or vaccines. We are interested in developing therapeutic or preventive vaccines for Chagas disease. We are using genomic tools, such as yeast surface display, to express T. cruzi genome-wide libraries to identify new epitopes for vaccine discovery. Moreover, we are using in immunology, genomics, and single-cell biology to understand the human and animal immune response to infection, focusing on potential vaccine protection mechanisms. We also explore these tools for target-based drug discovery to advance the therapeutic pipeline against Chagas disease.
Cestari I. Phosphoinositide signaling and regulation in Trypanosoma brucei: Specialized functions in a protozoan pathogen. PLoS Pathog. 2020. (Brief Review)
Cestari I, McLeland-Wieser H, Stuart K. Nuclear Phosphatidylinositol 5-Phosphatase Is Essential for Allelic Exclusion of Variant Surface Glycoprotein Genes in Trypanosomes. Mol Cell Biol. 2019
Cestari I, Stuart K., Transcriptional Regulation of Telomeric Expression Sites and Antigenic Variation in Trypanosomes. Curr Genomics. 2018 (Review)
Cestari I, Haas P, Moretti NS, Schenkman S, Stuart K., Chemogenetic Characterization of Inositol Phosphate Metabolic Pathway Reveals Druggable Enzymes for Targeting Kinetoplastid Parasites. Cell Chem Biol. 2016
Cestari I, Stuart K., Inositol phosphate pathway controls transcription of telomeric expression sites in trypanosomes. Proc Natl Acad Sci U S A. 2015