Igor Cestari

Assistant Professor

T: 514 398 8764  |  igor.cestari [at] mcgill.ca (Email)  |  Parasitology Building, P-212

Degrees

BSc (Federal University of Pernambuco)
MSc, PhD (Oswaldo Cruz Institute – Fiocruz)

Short Bio

Dr. Igor Cestari has a background in molecular and systems biology. He obtained his BS degree in biology with a specialty in genetics, and MSc and PhD degrees in molecular and cellular biology studying the mechanisms of complement system evasion by trypanosomes. During his postdoctoral training at the Center for Infectious Disease Research (Seattle), he investigated the molecular mechanisms underlying the control of antigenic variation in trypanosomes with a focus 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 cell signalling and transcriptional control mechanisms that govern antigenic variation and life stage development in trypanosomes.

Research Interests

Signal transduction and transcriptional control mechanisms that govern antigenic variation and life stage development in trypanosomes.

Current Research

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 there are a few drugs 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 the biology of these organisms for advancing strategies of disease control. We have three main research themes:

1) Allelic exclusion of variant surface glycoprotein genes and antigenic variation: T. brucei periodically switches its variant surface glycoprotein (VSG) coat to evade host antibody clearance. This parasite expresses only one of its ~2,000 VSG genes at a time, which is exclusively transcribed at one of the 20 telomeric expression sites (ESs). Antigenic variation of the surface coat occurs by transcriptional switching among telomeric ESs or by VSG gene recombination. The molecular mechanisms underlying the control of antigenic variation are poorly understood. However, it is known to entail three fundamental processes: allelic exclusion of VSG genes, a telomere position effect that silences some VSG genes, and transcriptional switching and recombination among VSG genes. We previously found that transcriptional control of VSG genes entails a multiprotein complex and is regulated by a phosphatidylinositol system (Cestari & Stuart, PNAS 2015). Our laboratory focuses on the cell signalling and transcriptional control processes that regulate expression and switching of VSG genes. These processes include control of RNA polymerase I transcription, organization of telomeric ES chromatin and structural organization of the nucleus during parasite growth and development.

2) Surface antigenic diversity and pathogen-host interaction: Trypanosoma cruzi have a large repertoire of genes (and pseudogenes) encoding mucin and mucin-associated surface proteins (MASPs), which are heterogeneously expressed in parasite populations. These genes contain hypervariable regions and produce highly O-glycosylated proteins that are potentially involved in host immune evasion and host cell interaction. We are interested in understanding the molecular mechanisms that control mucin and MASP expression and how their genetic and antigenic diversification contributes to parasite immune evasion and host cell interaction. We use CRISPR-Cas9 technology and single cell analysis to understand the transcriptional and post-transcriptional mechanisms that control mucin and MASP gene expression and to investigate the function of antigenic diversification in parasite-host cell interaction and immune evasion.

3) Signal transduction and regulation of cell development: T. brucei and related parasites (T. cruzi and Leishmania) undergo many developmental changes as they alternate between a mammalian host and the insect vector. These developmental processes include changes in cell morphology, surface composition, organelle function and metabolism to survive in the host and vector. Regulation of these processes requires dramatic changes in gene expression, which in trypanosomes are controlled primarily post-transcriptionally and by mechanisms that are incompletely understood. We have recently found that inositol phosphates are part of a regulatory system involved in the control of T. brucei life stage development, a process that involves cell signalling and post-transcriptional control of gene expression (Cestari et al., Mol Biol Cell 2018). Our laboratory is interested in the signal transduction system that controls the development of trypanosomes, particularly T. brucei, which we use as a model system. We use systems biology approaches to understand the mechanisms that control and integrate signalling and post-transcriptional processes to regulate parasite life stage development.

Publications

View a list of current publications.

Select publications

Cestari I, Stuart K., Transcriptional Regulation of Telomeric Expression Sites and Antigenic Variation in Trypanosomes. Curr Genomics. 2018 (Review)

Cestari I, Anupama A, Stuart K., Inositol polyphosphate multikinase regulation of Trypanosoma brucei life stage development. Mol Biol Cell. 2018

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