A5033544611- Tuberculosis Research and Epidemiology
- Mycobacterium research and diagnosis
- Malaria Research and Control
- Mosquito-borne diseases and control
- Infectious Diseases and Tuberculosis
- Drug Transport and Resistance Mechanisms
- Pneumocystis jirovecii pneumonia detection and treatment
- Antibiotic Resistance in Bacteria
- Diagnosis and treatment of tuberculosis
- Helminth infection and control
- Coccidia and coccidiosis research
- Immunodeficiency and Autoimmune Disorders
- Immune responses and vaccinations
- Invertebrate Immune Response Mechanisms
- Parasite Biology and Host Interactions
- Neonatal Respiratory Health Research
- Bacteriophages and microbial interactions
- Trypanosoma species research and implications
- Parasitic Infections and Diagnostics
- RNA and protein synthesis mechanisms
- Genomics and Phylogenetic Studies
- Computational Drug Discovery Methods
- Viral Infections and Vectors
- Ginseng Biological Effects and Applications
- Coral and Marine Ecosystems Studies
McGill University Health Centre
2013-2023
McGill University
2010-2023
North Carolina Agricultural and Technical State University
2023
Montreal General Hospital
2011
National Institutes of Health
2003-2007
Walter and Eliza Hall Institute of Medical Research
2000-2005
National Institute of Allergy and Infectious Diseases
2003-2005
The University of Melbourne
1998-2003
National Institute of Malariology, Parasitology and Entomology
2003
The Royal Melbourne Hospital
2000-2001
The genome sequence of Mycobacterium tuberculosis revealed the presence 12 membrane proteins proposed to have a function in transport lipids. Insertional inactivation 11 these has that only 1 (MmpL3) is apparently essential for viability. Five are conserved within leprae. drug susceptibilities mutants broad spectrum agents unaltered, suggesting unlike their other organisms, do not play significant role intrinsic resistance. Each was assessed growth kinetics and lethality murine low-dose...
Infection with Mycobacterium tuberculosis in humans results active disease approximately 10% of immune-competent individuals, the most-severe clinical manifestations observed when bacilli infect central nervous system (CNS). Here, we use a rabbit model tuberculous meningitis to evaluate severity caused by M. isolates CDC1551, highly immunogenic strain, and HN878 or W4, 2 members W/Beijing family strains. Compared infection CNS W4 resulted higher bacillary loads cerebrospinal fluid brain,...
The Beijing family of Mycobacterium tuberculosis strains has been associated with epidemic spread and an increased likelihood developing drug resistance. characteristics that predispose this to such clinical outcomes have not identified, although one potential candidate, the phenolic glycolipid PGL-tb, shown mediate a fulminant lethal disease in mice rabbits due lipid-mediated immunosuppression. However, PGL-tb is uniformly expressed throughout lineage may be only unique virulence trait...
Peptidoglycan-derived muramyl dipeptide (MDP) activates innate immunity via the host sensor NOD2. Although MDP is N-acetylated in most bacteria, mycobacteria and related Actinomycetes convert their to an N-glycolylated form through action of N-acetyl muramic acid hydroxylase (NamH). We used a combination bacterial genetics synthetic chemistry investigate whether N-glycolylation alters NOD2-mediated immunity. Upon infecting macrophages with 12 tumor necrosis factor (TNF) α secretion was NOD2...
In vitro infection of monocytes with Mycobacterium tuberculosis HN878 and related W/Beijing isolates preferentially induced interleukin-4 (IL-4) IL-13, which characterize Th2 polarized immunity. contrast, CDC1551 more IL-12 other molecules associated phagocyte activation Th1 protective The differential cytokine-chemokine response was mediated by extracted lipids, suggesting that these regulate host responses to infection.
Erythrocyte invasion by Plasmodium requires molecules present both on the merozoite surface and within specialized organelles of apical complex. The erythrocyte binding protein family includes falciparum sialic acid-binding protein, EBA-175 (erythrocyte antigen-175), which binds acid glycophorin A human erythrocytes. We address role conserved 3′-cysteine rich region, transmembrane, cytoplasmic domains through targeted gene disruption. Truncation had no measurable effect either level...
ABSTRACT Over recent years, there has been an increasing acknowledgment of the diversity that exists among Mycobacterium tuberculosis clinical isolates. To facilitate comparative studies aimed at deciphering relevance this to human disease, unambiguous and easily interpretable method strain classification is required. Presently, most effective means assigning isolates into a series lineages Gagneux et al. (S. al., Proc. Natl. Acad. Sci. USA 103:2869-2873, 2006) involves PCR-based detection...
Isolated in vitro more than half a century ago, the H37Rv strain of Mycobacterium tuberculosis still remains choice for majority laboratories conducting vivo studies TB pathogenesis. In this report we reveal that is highly prone to losing ability synthesize cell wall lipid phthiocerol dimycocerosate (PDIM) during extended periods culture. addition, stocks have been held even short length time should be thought as heterogeneous population PDIM-positive and PDIM-negative types. We demonstrate...
ABSTRACT It has long been held that the malaria parasite, Plasmodium sp., is incapable of de novo fatty acid synthesis. This view recently overturned with emergence data for presence a biosynthetic pathway in relict plastid P. falciparum (known as apicoplast). represents type II common to plant chloroplasts and bacteria but distinct from I animals including humans. Specific inhibitors pathway, thiolactomycin triclosan, have reported target this pathway. Here we report further plastid-based...
To study the role of MmpL8-mediated lipid transport in sulfatide biogenesis, we insertionally inactivated mmpL8 gene Mycobacterium tuberculosis. Characterization this strain showed that synthesis mature sulfolipid SL-1 was interrupted and a more polar sulfated molecule, termed SL-N, accumulated within cell. Purification SL-N structural analysis identified molecule as family 2,3-diacyl-α,α′-d-trehalose-2′-sulfates. This structure suggests biogenesis are coupled final step biosynthesis may be...
Invasion of the merozoite form Plasmodium falciparum into human erythrocytes involves multiple receptor–ligand interactions. The EBA175 protein P. has been shown to be ligand that binds a sialic acid‐dependent site on glycophorin A. We have identified novel ligand, termed erythrocyte‐binding antigen 140 (EBA140), shares structural features and homology with EBA175. Subcellular localization EBA140 suggests it is located in micronemes, same as receptor surface erythrocytes. Binding this...
Between November 2011 and 2012, a Canadian village of 933 persons had 50 culture-positive cases tuberculosis, with 49 sharing the same genotype.We performed Illumina-based whole-genome sequencing on Mycobacterium tuberculosis isolates from this village, during before outbreak. Phylogenetic trees were generated using maximum likelihood method.Three distinct genotypes identified. Strain I (n = 7) was isolated in 1991-1996. II 8) 1996-2004. III 62) first appeared 2007 did not arise strain or...
Mycobacteria are well known for their taxonomic diversity, impact on global health, and atypical cell wall envelope. In addition to a cytoplasmic membrane peptidoglycan layer, the envelope of members order Corynebacteriales, which include Mycobacterium tuberculosis, also have an arabinogalactan layer connecting outer membrane, so-called "mycomembrane". This unusual composition mycobacteria is prime importance several physiological processes such as protection from external stresses...
Background Mycobacterium tuberculosis (MTB) has been classified into 4 main lineages. Some reports have associated certain lineages with particular clinical phenotypes, but there is still insufficient information regarding the and epidemiologic implications of MTB lineage variation. Methods Using large sequence polymorphisms we isolates from a population-based study in Montreal, Canada major lineages, identified features. In addition, IS6110-RFLP spoligotyping were used as indicators recent...
The invasion of host cells by the malaria parasite Plasmodium falciparum requires specific protein–protein interactions between and receptors an intracellular translocation machinery to power process. transmembrane erythrocyte binding protein-175 (EBA-175) thrombospondin-related anonymous protein (TRAP) play central roles in this EBA-175 binds glycophorin A on human erythrocytes during process, linking surface cell. In report, we show that cytoplasmic domain encodes crucial information for...
ABSTRACT As part of our effort to uncover the molecular basis for phenotypic variation among clinical Mycobacterium tuberculosis isolates, we have previously reported that isolates belonging W/Beijing lineage constitutively overexpress DosR-regulated transcriptional program. While generating dosR knockouts in two independent sublineages, were surprised discover they possess copies . This amplification is a massive genomic duplication spanning 350 kb and encompassing >300 genes. In total,...
Mycobacteria produce an unusual, glycolylated form of muramyl dipeptide (MDP) that is more potent and efficacious at inducing NOD2-mediated host responses. We tested the importance this modified MDP in Mycobacterium tuberculosis by disrupting gene, namH, responsible for modification. In vitro, namH mutant did not N-glycolylated muropeptides, but there was no alteration colony morphology, growth kinetics, cellular or mycolic acid profile. Ex vivo, survived replicated normally murine human...
ABSTRACT The DosR regulon, a set of 48 genes normally expressed in Mycobacterium tuberculosis under conditions that inhibit aerobic respiration, is controlled via the DosR-DosS/DosT two-component system. While regulon requires induction most M. isolates, for members Beijing lineage, its expression uncoupled from need signaling. In our attempts to understand mechanistic basis this uncoupling background, we previously reported identification two synonymous single-nucleotide polymorphisms...
Clinical isolates of Mycobacterium tuberculosis demonstrate significant heterogeneity in virulence potential animal models infection. Isolate CDC1551, for example, has previously been described mouse survival studies as being hypovirulent, and isolate HN878 hypervirulent. Observed differences this infection experiment have proposed to reflect differential engagement the host immune response. To assess whether is a local or systemic effect, C57BL/6 mice were infected simultaneously with...
As part of our ongoing efforts to uncover the phenotypic consequences genetic variability among clinical Mycobacterium tuberculosis isolates, we previously reported that isolates "East Asian" or "W/Beijing" lineage constitutively overexpress coordinately regulated transcriptional program known as DosR regulon under standard in vitro conditions. This phenotype distinguishes W/Beijing from all other M. lineages, which normally induce expression this only once exposed low oxygen nitric oxide,...