A5017391390- Tuberculosis Research and Epidemiology
- Mycobacterium research and diagnosis
- Biochemical and Molecular Research
- Autophagy in Disease and Therapy
- Cancer therapeutics and mechanisms
- Calcium signaling and nucleotide metabolism
- Enzyme Structure and Function
- Infectious Diseases and Tuberculosis
- Antibiotic Resistance in Bacteria
- Click Chemistry and Applications
- RNA and protein synthesis mechanisms
- Microbial Metabolic Engineering and Bioproduction
- Cell Image Analysis Techniques
- Bacterial Genetics and Biotechnology
- Peptidase Inhibition and Analysis
- Cancer-related gene regulation
- CRISPR and Genetic Engineering
- Biotin and Related Studies
- Sphingolipid Metabolism and Signaling
- Immune cells in cancer
- Immune responses and vaccinations
- Invertebrate Immune Response Mechanisms
- Immunodeficiency and Autoimmune Disorders
- Quinazolinone synthesis and applications
- Peroxisome Proliferator-Activated Receptors
Cornell University
2017-2024
Weill Cornell Medicine
2017-2024
The Francis Crick Institute
2020-2023
Université de Toulouse
2009
Laboratoire d'Ingénierie des Systèmes Biologiques et des Procédés
2009
Forschungszentrum Jülich
2009
Institut de Pharmacologie et de Biologie Structurale
2006
Autophagy is a cellular innate-immune defence mechanism against intracellular microorganisms, including Mycobacterium tuberculosis (Mtb). How canonical and non-canonical autophagy function to control Mtb infection in phagosomes the cytosol remains unresolved. Macrophages are main host cell humans for Mtb. Here we studied contributions of genetically tractable human induced pluripotent stem cell-derived macrophages (iPSDM), using set mutants generated same genetic background common lab strain...
Induction of lipid-laden foamy macrophages is a cellular hallmark tuberculosis (TB) disease, which involves the transformation infected phagolysosomes from site killing into nutrient-rich replicative niche. Here, we show that terpenyl nucleoside shed Mycobacterium tuberculosis, 1-tuberculosinyladenosine (1-TbAd), caused lysosomal maturation arrest and autophagy blockade, leading to lipid storage in M1 macrophages. Pure 1-TbAd, or infection with nucleoside-producing M. intralysosomal...
Toxin-antitoxin (TA) systems regulate fundamental cellular processes in bacteria and represent potential therapeutic targets. We report a new RES-Xre TA system multiple human pathogens, including Mycobacterium tuberculosis. The toxin, MbcT, is bactericidal unless neutralized by its antitoxin MbcA. To investigate the mechanism, we solved 1.8 Å-resolution crystal structure of MbcTA complex. found that MbcT resembles secreted NAD+-dependent bacterial exotoxins, such as diphtheria toxin. Indeed,...
Abstract Rifampicin, which inhibits bacterial RNA polymerase, provides one of the most effective treatments for tuberculosis. Inhibition transcription termination factor Rho is used to treat some infections, but its importance varies across bacteria. Here we show that Mycobacterium tuberculosis functions both define 3′ ends mRNAs and silence substantial fragments genome. Brief inactivation affects over 500 transcripts enriched genes foreign DNA elements virulence factors. Prolonged causes...
Peroxisomes are organelles involved in many metabolic processes including lipid metabolism, reactive oxygen species (ROS) turnover, and antimicrobial immune responses. However, the cellular mechanisms by which peroxisomes contribute to bacterial elimination macrophages remain elusive. Here, we investigated peroxisome function iPSC-derived human (iPSDM) during infection with Mycobacterium tuberculosis (Mtb). We discovered that Mtb-triggered biogenesis requires ESX-1 type 7 secretion system,...
Abstract Tuberculous granulomas are the sites of interaction between host response and tubercle bacilli within infected individuals. They mainly consist organized aggregations lymphocytes macrophages (Mf). A predominant role mycobacterial envelope glycolipids in formation has been recently emphasized, yet signaling events interfering with granuloma cell differentiation remain elusive. To decipher this molecular machinery, we have developed an vitro human model granulomas. In study, provide...
Mycobacterium tuberculosis contains >20 enzymes that require activation by transfer of the 4′-phosphopantetheine moiety CoA onto a conserved serine residue, posttranslational modification catalyzed 4′-phosphopantetheinyl transferases (PPTases). The modified proteins are involved in key metabolic processes such as cell envelope biogenesis and production virulence factors. We show two PPTases all spp. related genera activate different subsets not functionally redundant. One enzyme, AcpS,...
Mycobacterium tuberculosis segregates within multiple subcellular niches with different biochemical and biophysical properties that, upon treatment, may impact antibiotic distribution, accumulation, efficacy. However, it remains unclear whether fluctuating intracellular microenvironments alter mycobacterial homeostasis contribute to enrichment Here, we describe a live dual-imaging approach monitor host acidification M. intrabacterial pH. By combining this pharmacological genetic...
Abstract Of the ~80 putative toxin‐antitoxin (TA) modules encoded by bacterial pathogen Mycobacterium tuberculosis ( Mtb ), three contain antitoxins essential for viability. One of these, Rv0060 (DNA ADP‐ribosyl glycohydrolase, DarG functions along with its cognate toxin Rv0059 transferase, DarT to mediate reversible DNA ADP‐ribosylation (Jankevicius et al ., 2016). We demonstrate that ‐DarG form a functional TA pair and essentiality darG is dependent on presence darT , but simultaneous...
The Mycobacterium tuberculosis complex (MTBC) is a group of related pathogens that cause (TB) in mammals. MTBC species are distinguished by their ability to sustain distinct host populations. While bovis (Mbv) sustains transmission cycles cattle and wild animals causes zoonotic TB, M. (Mtb) affects human populations seldom disease cattle. pathogen determinants underlying tropism between still unknown. Macrophages the main cell encounters mycobacteria upon initial infection, we hypothesised...
Intracellular pathogens such as Mycobacterium tuberculosis (Mtb) have evolved diverse strategies to counteract macrophage defence mechanisms including phagolysosomal biogenesis. Within macrophages, Mtb initially resides inside membrane-bound phagosomes that interact with lysosomes and become acidified. The ability of control subvert the fusion between plays a key role in pathogenesis tuberculosis. Therefore, understanding how endolysosomal network cope intracellular acidification is...
Lipid biosynthesis in the pathogen Mycobacterium tuberculosis depends on biotin for posttranslational modification of key enzymes. However, mycobacterial synthetic pathway is not fully understood. Here, we show that rv1590, a gene previously unknown function, required by M. to synthesize biotin. Chemical-generic interaction experiments mapped function rv1590 conversion dethiobiotin biotin, which catalyzed synthases (BioB). Biochemical studies confirmed contrast BioB Escherichia coli,...
Genome sequence information suggests that B(12)-dependent mutases are present in a number of bacteria, including members the suborder Corynebacterineae like Mycobacterium tuberculosis and Corynebacterium glutamicum. We here functionally identify methylmalonyl coenzyme A (CoA) mutase C. glutamicum is retained all encoded by NCgl1471, NCgl1472, NCgl1470. In addition, we observe presence methylmalonate glutamicum, reaching concentrations up to 757 nmol g (dry weight)(-1) propionate-grown cells,...
Treatment of Mycobacterium tuberculosis and avium infections requires multiple drugs for long time periods. protein-tyrosine-phosphatase B (MptpB) is a key M. virulence factor that subverts host antimicrobial activity to promote intracellular survival. Inhibition MptpB reduces the infection burden in vivo offers new opportunities improve current treatments. Here, we demonstrate produces an orthologue inhibitor C13 macrophages. Combining with antibiotics rifampicin or bedaquiline showed...
Summary The intracellular population of Mycobacterium tuberculosis (Mtb) is dynamically segregated within multiple subcellular niches with different biochemical and biophysical properties that, upon treatment, may impact antibiotic distribution, accumulation, efficacy. However, it remains unclear whether fluctuating microenvironments alter mycobacterial homeostasis contribute to enrichment Here, we describe a dual-imaging approach that allows quantitative monitoring host acidification Mtb...
Abstract The Mycobacterium tuberculosis complex (MTBC) is a group of related pathogens that cause (TB) in mammals. MTBC species are distinguished by their ability to sustain distinct host populations. While bovis (Mbv) sustains transmission cycles cattle and wild animals causes zoonotic TB, M. (Mtb) affects human populations seldom disease cattle. However, the pathogen determinants driving tropism between still unknown. Macrophages main cell encounters mycobacteria upon initial infection we...