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Sassetti, Christopher

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overview	Academic Background: Ph.D. University of California, San Francisco, CA. 2000 Damon Runyon Foundation Scholar (www.damonrunyon.org) Pathogenesis of tuberculosis Mycobacterium tuberculosis is often called the world's most successful pathogen. It is estimated that one third of the human population has been exposed to this organism, and tuberculosis (TB) kills millions every year. Unlike many other bacterial pathogens that cause acute disease and replicate only in a specific host niche, M. tuberculosis can maintain a chronic infection by adapting to many distinctly different host microenvironments. Our lab is focused on defining the survival strategies used by this pathogen in each of these environments. To this end, we have developed a variety of new methodologies, which take advantage of both classical genetic tools and genome sequence information. Using these methods, we have identified hundreds of mycobacterial genes that are specifically required for the bacterium to survive under a variety of conditions including acute and chronic infection models. Current work is focused on the characterizing the functional roles played by these virulence systems. Specific projects include: 1)Understanding how nutrients are acquired in vivo. M. tuberculosis resides largely within a membrane bound compartment during infection, and it remains unclear how the bacterium acquires nutrients in this apparently isolated niche. We have identified a series of lipid and carbohydrate import systems that are critical for growth during specific phases of disease. One of these functions as a sterol uptake system, which has lead to the discovery that host cholesterol is an essential carbon source during chronic infection (see figure). We are currently focused on defining the mechanisms by which the bacterium extracts and degrades nutrients, such as cholesterol, from the host cell and understanding why the nutritional habits of the bacterium change so dramatically as disease progresses. RFP-labeledM. tuberculosis resides in cholesterol rich regions of the cell (green). 2)Understanding the unique physiology of the mycobacterial cell wall. The cell envelope of M. tuberculosis forms a unique barrier to environmental insults and is essential for the viability of the pathogen. Using a combination of high-throughput genetic, biochemical and structural approaches, we are investigating how phosphosignaling cascades regulate the synthesis of this complex structure. Cell wall synthesis (green) is dysregulated in mycobacterial mutants compared to wild type cells (red). 3)Metabolic regulation of cell growth and antibiotic sensitivity. The immune system of the host exerts a variety of stresses on the bacterium, which cause it to stop replicating and become refractory to antibiotic treatment. Using a combination of genetic and metabolomic approaches, we are defining the mechanisms by which M. tuberculosis senses these stresses and responds by reducing its growth and metabolic rate. To see information on the Sassetti Lab .
Summary	Focus: Pathogenesis of tuberculosis

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overview

Academic Background:

Ph.D. University of California, San Francisco, CA. 2000
Damon Runyon Foundation Scholar (www.damonrunyon.org)

Pathogenesis of tuberculosis

Mycobacterium tuberculosis is often called the world's most successful pathogen. It is estimated that one third of the human population has been exposed to this organism, and tuberculosis (TB) kills millions every year. Unlike many other bacterial pathogens that cause acute disease and replicate only in a specific host niche, M. tuberculosis can maintain a chronic infection by adapting to many distinctly different host microenvironments. Our lab is focused on defining the survival strategies used by this pathogen in each of these environments.

To this end, we have developed a variety of new methodologies, which take advantage of both classical genetic tools and genome sequence information. Using these methods, we have identified hundreds of mycobacterial genes that are specifically required for the bacterium to survive under a variety of conditions including acute and chronic infection models. Current work is focused on the characterizing the functional roles played by these virulence systems.

Specific projects include:

1)Understanding how nutrients are acquired in vivo. M. tuberculosis resides largely within a membrane bound compartment during infection, and it remains unclear how the bacterium acquires nutrients in this apparently isolated niche. We have identified a series of lipid and carbohydrate import systems that are critical for growth during specific phases of disease. One of these functions as a sterol uptake system, which has lead to the discovery that host cholesterol is an essential carbon source during chronic infection (see figure). We are currently focused on defining the mechanisms by which the bacterium extracts and degrades nutrients, such as cholesterol, from the host cell and understanding why the nutritional habits of the bacterium change so dramatically as disease progresses.

RFP-labeledM. tuberculosis resides in
cholesterol rich regions of the cell (green).

2)Understanding the unique physiology of the mycobacterial cell wall. The cell envelope of M. tuberculosis forms a unique barrier to environmental insults and is essential for the viability of the pathogen. Using a combination of high-throughput genetic, biochemical and structural approaches, we are investigating how phosphosignaling cascades regulate the synthesis of this complex structure.

Cell wall synthesis (green) is dysregulated in mycobacterial mutants compared to wild type cells (red).

3)Metabolic regulation of cell growth and antibiotic sensitivity. The immune system of the host exerts a variety of stresses on the bacterium, which cause it to stop replicating and become refractory to antibiotic treatment. Using a combination of genetic and metabolomic approaches, we are defining the mechanisms by which M. tuberculosis senses these stresses and responds by reducing its growth and metabolic rate.

To see information on the Sassetti Lab .

Summary

Focus: Pathogenesis of tuberculosis

One or more keywords matched the following items that are connected to Sassetti, Christopher

Item Type	Name
Academic Article	A new site-specific integration system for mycobacteria.
Academic Article	Characterization of mycobacterial virulence genes through genetic interaction mapping.
Academic Article	Transposon site hybridization in Mycobacterium tuberculosis.
Academic Article	Nitrile-inducible gene expression in mycobacteria.
Academic Article	NOD2, RIP2 and IRF5 play a critical role in the type I interferon response to Mycobacterium tuberculosis.
Academic Article	Variation among genome sequences of H37Rv strains of Mycobacterium tuberculosis from multiple laboratories.
Academic Article	Relics of selection in the mycobacterial genome.
Academic Article	Mycobacterium tuberculosis induces an atypical cell death mode to escape from infected macrophages.
Academic Article	High-resolution phenotypic profiling defines genes essential for mycobacterial growth and cholesterol catabolism.
Academic Article	Nitric oxide controls the immunopathology of tuberculosis by inhibiting NLRP3 inflammasome-dependent processing of IL-1?.
Academic Article	Bayesian analysis of gene essentiality based on sequencing of transposon insertion libraries.
Academic Article	Genes required for mycobacterial growth defined by high density mutagenesis.
Academic Article	Genetic requirements for mycobacterial survival during infection.
Academic Article	The folate pathway is a target for resistance to the drug para-aminosalicylic acid (PAS) in mycobacteria.
Academic Article	Mutually dependent secretion of proteins required for mycobacterial virulence.
Academic Article	The open book of infectious diseases.
Academic Article	NOD2 pathway activation by MDP or Mycobacterium tuberculosis infection involves the stable polyubiquitination of Rip2.
Academic Article	Mycobacterial persistence requires the utilization of host cholesterol.
Academic Article	igr Genes and Mycobacterium tuberculosis cholesterol metabolism.
Academic Article	Phthiocerol dimycocerosate transport is required for resisting interferon-gamma-independent immunity.
Academic Article	Role of cholesterol in Mycobacterium tuberculosis infection.
Academic Article	Metabolic regulation of mycobacterial growth and antibiotic sensitivity.
Academic Article	A phosphorylated pseudokinase complex controls cell wall synthesis in mycobacteria.
Academic Article	Cholesterol catabolism by Mycobacterium tuberculosis requires transcriptional and metabolic adaptations.
Academic Article	Cyclic AMP regulation of protein lysine acetylation in Mycobacterium tuberculosis.
Academic Article	Global assessment of genomic regions required for growth in Mycobacterium tuberculosis.
Academic Article	A novel P(1B)-type Mn2+-transporting ATPase is required for secreted protein metallation in mycobacteria.
Academic Article	DNA methylation impacts gene expression and ensures hypoxic survival of Mycobacterium tuberculosis.
Concept	Mycobacterium tuberculosis
Concept	Latent Tuberculosis
Concept	Tuberculosis
Concept	Tuberculosis, Multidrug-Resistant
Concept	Tuberculosis, Pulmonary
Concept	Tuberculosis Vaccines
Academic Article	Identification of new drug targets and resistance mechanisms in Mycobacterium tuberculosis.
Academic Article	Differential roles for the Co(2+) /Ni(2+) transporting ATPases, CtpD and CtpJ, in Mycobacterium tuberculosis virulence.
Academic Article	Immunology: Fixing the odds against tuberculosis.
Academic Article	Biochemical and spatial coincidence in the provisional Ser/Thr protein kinase interaction network of Mycobacterium tuberculosis.
Academic Article	Allele-specific induction of IL-1? expression by C/EBP? and PU.1 contributes to increased tuberculosis susceptibility.
Academic Article	New TB treatments hiding in plain sight.
Academic Article	Identifying essential genes in Mycobacterium tuberculosis by global phenotypic profiling.
Academic Article	New insights into TB physiology suggest untapped therapeutic opportunities.
Academic Article	Mycobacterial recombineering.
Academic Article	Label-free Quantitative Proteomics Reveals a Role for the Mycobacterium tuberculosis SecA2 Pathway in Exporting Solute Binding Proteins and Mce Transporters to the Cell Wall.
Academic Article	The Oxidative Stress Network of Mycobacterium tuberculosis Reveals Coordination between Radical Detoxification Systems.
Academic Article	Phosphorylation of the Peptidoglycan Synthase PonA1 Governs the Rate of Polar Elongation in Mycobacteria.
Academic Article	Peptidoglycan synthesis in Mycobacterium tuberculosis is organized into networks with varying drug susceptibility.
Academic Article	Chewing the fat: lipid metabolism and homeostasis during M. tuberculosis infection.
Academic Article	Fine-tuning of Substrate Affinity Leads to Alternative Roles of Mycobacterium tuberculosis Fe2+-ATPases.
Academic Article	A cytoplasmic peptidoglycan amidase homologue controls mycobacterial cell wall synthesis.
Academic Article	xCT increases tuberculosis susceptibility by regulating antimicrobial function and inflammation.
Academic Article	Tuberculosis Susceptibility and Vaccine Protection Are Independently Controlled by Host Genotype.
Academic Article	Structural and Genetic Analyses of the Mycobacterium tuberculosis Protein Kinase B Sensor Domain Identify a Potential Ligand-binding Site.
Academic Article	Comprehensive Essentiality Analysis of the Mycobacterium tuberculosis Genome via Saturating Transposon Mutagenesis.
Academic Article	Programmable transcriptional repression in mycobacteria using an orthogonal CRISPR interference platform.
Academic Article	Statistical analysis of genetic interactions in Tn-Seq data.
Academic Article	Nitric oxide prevents a pathogen-permissive granulocytic inflammation during tuberculosis.
Academic Article	A Lysine Acetyltransferase Contributes to the Metabolic Adaptation to Hypoxia in Mycobacterium tuberculosis.
Academic Article	Consequence of enhanced LC3-trafficking for a live, attenuated M. tuberculosis vaccine.
Academic Article	Mycobacterium tuberculosis is protected from NADPH oxidase and LC3-associated phagocytosis by the LCP protein CpsA.
Academic Article	Tolerating the Unwelcome Guest; How the Host Withstands Persistent Mycobacterium tuberculosis.
Academic Article	The Phagocyte Oxidase Controls Tolerance to Mycobacterium tuberculosis Infection.
Academic Article	Modeling Diversity: Do Homogeneous Laboratory Strains Limit Discovery?
Academic Article	Role of Granulocyte-Macrophage Colony-Stimulating Factor Production by T Cells during Mycobacterium tuberculosis Infection.
Academic Article	ORBIT: a New Paradigm for Genetic Engineering of Mycobacterial Chromosomes.
Academic Article	Large-scale chemical-genetics yields new M. tuberculosis inhibitor classes.
Academic Article	Common Variants in the Glycerol Kinase Gene Reduce Tuberculosis Drug Efficacy.
Academic Article	Statistical analysis of variability in TnSeq data across conditions using zero-inflated negative binomial regression.
Academic Article	Functionally Overlapping Variants Control Tuberculosis Susceptibility in Collaborative Cross Mice.
Academic Article	Tuberculosis vaccine finds an improved route.
Academic Article	Evaluation of IL-1 Blockade as an Adjunct to Linezolid Therapy for Tuberculosis in Mice and Macaques.
Academic Article	Granulocytes act as a niche for Mycobacterium tuberculosis growth.
Academic Article	CD11cHi?monocyte-derived macrophages are a major cellular compartment infected by Mycobacterium tuberculosis.
Academic Article	Distinct Bacterial Pathways Influence the Efficacy of Antibiotics against Mycobacterium tuberculosis.
Academic Article	Cell-Cycle-Associated Expression Patterns Predict Gene Function in Mycobacteria.
Academic Article	A natural polymorphism of Mycobacterium tuberculosis in the esxH gene disrupts immunodomination by the TB10.4-specific CD8 T cell response.
Academic Article	M.?tuberculosis Reprograms Hematopoietic Stem Cells to Limit Myelopoiesis and Impair Trained Immunity.
Academic Article	Two-Way Regulation of MmpL3 Expression Identifies and Validates Inhibitors of MmpL3 Function in Mycobacterium tuberculosis.
Academic Article	Sirtuin 3 Downregulation in Mycobacterium tuberculosis-Infected Macrophages Reprograms Mitochondrial Metabolism and Promotes Cell Death.
Academic Article	Host immunity increases Mycobacterium tuberculosis reliance on cytochrome bd oxidase.
Academic Article	Characterization of Drug-Resistant Lipid-Dependent Differentially Detectable Mycobacterium tuberculosis.
Academic Article	An improved statistical method to identify chemical-genetic interactions by exploiting concentration-dependence.
Academic Article	Host-pathogen genetic interactions underlie tuberculosis susceptibility in genetically diverse mice.
Academic Article	REL and BHLHE40 Variants Are Associated with IL-12 and IL-10 Responses and Tuberculosis Risk.
Academic Article	Chemical-genetic interaction mapping links carbon metabolism and cell wall structure to tuberculosis drug efficacy.
Academic Article	Differential Requirement for IRGM Proteins during Tuberculosis Infection in Mice.
Academic Article	Mycobacterium tuberculosis Evasion of Guanylate Binding Protein-Mediated Host Defense in Mice Requires the ESX1 Secretion System.
Academic Article	Genome-wide screen identifies host loci that modulate M. tuberculosis fitness in immunodivergent mice.
Academic Article	High Bacillary Burden and the ESX-1 Type VII Secretion System Promote MHC Class I Presentation by Mycobacterium tuberculosis-Infected Macrophages to CD8 T Cells.
Academic Article	Host genetic background is a barrier to broadly effective vaccine-mediated protection against tuberculosis.
Academic Article	Phase variation as a major mechanism of adaptation in Mycobacterium tuberculosis complex.
Academic Article	Genome-wide screen identifies host loci that modulate Mycobacterium tuberculosis fitness in immunodivergent mice.
Academic Article	The Rip1 intramembrane protease contributes to iron and zinc homeostasis in Mycobacterium tuberculosis.
Academic Article	Glycerol contributes to tuberculosis susceptibility in male mice with type 2 diabetes.
Academic Article	Differentiating the roles of Mycobacterium tuberculosis substrate binding proteins, FecB and FecB2, in iron uptake.
Academic Article	The structure of Mycobacterium thermoresistibile MmpS5 reveals a conserved disulfide bond across mycobacteria.
Academic Article	Multiple genetic loci influence vaccine-induced protection against Mycobacterium tuberculosis in genetically diverse mice.
Academic Article	Genome-wide screen of Mycobacterium tuberculosis- infected macrophages identified the GID/CTLH complex as a determinant of intracellular bacterial growth.
Academic Article	Impaired fatty acid import or catabolism in macrophages restricts intracellular growth of Mycobacterium tuberculosis.
Academic Article	Mycobacterium tuberculosis virulence lipid PDIM inhibits autophagy in mice.
Academic Article	Chemical genetic interactions elucidate pathways controlling tuberculosis antibiotic efficacy during infection.
Academic Article	Genome-wide screen of Mycobacterium tuberculosis-infected macrophages revealed GID/CTLH complex-mediated modulation of bacterial growth.

Search Criteria

Tuberculosis