Sign in to edit your profile (add interests, mentoring, photo, etc.)
    Keywords
    Last Name
    Institution

    Christopher M Sassetti PhD

    AddressUniversity of Massachusetts Medical School
    55 Lake Avenue North, S6-141
    Worcester MA 01655
    Phone508-856-3678
        Overview 
        Narrative

        Academic Background:

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

        Other:

        Howard Hughes Medical Institute Investigator (www.hhmi.org)

        Pathogenesis of tuberculosis

        Christopher Sassetti, Ph.D.

        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.

        Cholesterol

        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 Systhesis

        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 .

        For more information, visit hisHoward Hughes Medical Institute web page.



        Rotation Projects

        Rotation Projects

        We have identified a number of bacterial pathways that are required for bacterial viability or virulence. We are particularly interested in:

        1. Phosphosignaling systems that regulate cell wall synthesis
        2. Metabolic regulatory mechanisms that trigger the “dormancy” response observed during infection.

        A variety of genetic, biochemical, and informatic methods will be used to define the functions of these genes and the role played by each during infection.



        Bibliographic 
        selected publications
        List All   |   Timeline
        1. Meniche X, Otten R, Siegrist MS, Baer CE, Murphy KC, Bertozzi CR, Sassetti CM. Subpolar addition of new cell wall is directed by DivIVA in mycobacteria. Proc Natl Acad Sci U S A. 2014 Aug 5; 111(31):E3243-51.
          View in: PubMed
        2. Behar SM, Sassetti CM. Immunology: Fixing the odds against tuberculosis. Nature. 2014 Jul 3; 511(7507):39-40.
          View in: PubMed
        3. Raimunda D, Long JE, Padilla-Benavides T, Sassetti CM, Argüello JM. Differential roles for the Co(2+) /Ni(2+) transporting ATPases, CtpD and CtpJ, in Mycobacterium tuberculosis virulence. Mol Microbiol. 2014 Jan; 91(1):185-97.
          View in: PubMed
        4. Ioerger TR, O'Malley T, Liao R, Guinn KM, Hickey MJ, Mohaideen N, Murphy KC, Boshoff HI, Mizrahi V, Rubin EJ, Sassetti CM, Barry CE, Sherman DR, Parish T, Sacchettini JC. Identification of New Drug Targets and Resistance Mechanisms in Mycobacterium tuberculosis. PLoS One. 2013; 8(9):e75245.
          View in: PubMed
        5. Shell SS, Prestwich EG, Baek SH, Shah RR, Sassetti CM, Dedon PC, Fortune SM. DNA methylation impacts gene expression and ensures hypoxic survival of Mycobacterium tuberculosis. PLoS Pathog. 2013; 9(7):e1003419.
          View in: PubMed
        6. Rittershaus ES, Baek SH, Sassetti CM. The normalcy of dormancy: common themes in microbial quiescence. Cell Host Microbe. 2013 Jun 12; 13(6):643-51.
          View in: PubMed
        7. O'Sullivan BP, Sassetti CM. Infection control in cystic fibrosis: share and share alike. Lancet. 2013 May 4; 381(9877):1517-9.
          View in: PubMed
        8. Padilla-Benavides T, Long JE, Raimunda D, Sassetti CM, Argüello JM. A novel P(1B)-type Mn2+-transporting ATPase is required for secreted protein metallation in mycobacteria. J Biol Chem. 2013 Apr 19; 288(16):11334-47.
          View in: PubMed
        9. DeJesus MA, Zhang YJ, Sassetti CM, Rubin EJ, Sacchettini JC, Ioerger TR. Bayesian analysis of gene essentiality based on sequencing of transposon insertion libraries. Bioinformatics. 2013 Mar 15; 29(6):695-703.
          View in: PubMed
        10. Mishra BB, Rathinam VA, Martens GW, Martinot AJ, Kornfeld H, Fitzgerald KA, Sassetti CM. Nitric oxide controls the immunopathology of tuberculosis by inhibiting NLRP3 inflammasome-dependent processing of IL-1ß. Nat Immunol. 2013 Jan; 14(1):52-60.
          View in: PubMed
        11. Zhang YJ, Ioerger TR, Huttenhower C, Long JE, Sassetti CM, Sacchettini JC, Rubin EJ. Global assessment of genomic regions required for growth in Mycobacterium tuberculosis. PLoS Pathog. 2012 Sep; 8(9):e1002946.
          View in: PubMed
        12. Lee HJ, Lang PT, Fortune SM, Sassetti CM, Alber T. Cyclic AMP regulation of protein lysine acetylation in Mycobacterium tuberculosis. Nat Struct Mol Biol. 2012 Aug; 19(8):811-8.
          View in: PubMed
        13. Raimunda D, Long JE, Sassetti CM, Argüello JM. Role in metal homeostasis of CtpD, a Co²? transporting P(1B4)-ATPase of Mycobacterium smegmatis. Mol Microbiol. 2012 Jun; 84(6):1139-49.
          View in: PubMed
        14. Griffin JE, Pandey AK, Gilmore SA, Mizrahi V, McKinney JD, Bertozzi CR, Sassetti CM. Cholesterol catabolism by Mycobacterium tuberculosis requires transcriptional and metabolic adaptations. Chem Biol. 2012 Feb 24; 19(2):218-27.
          View in: PubMed
        15. Gee CL, Papavinasasundaram KG, Blair SR, Baer CE, Falick AM, King DS, Griffin JE, Venghatakrishnan H, Zukauskas A, Wei JR, Dhiman RK, Crick DC, Rubin EJ, Sassetti CM, Alber T. A phosphorylated pseudokinase complex controls cell wall synthesis in mycobacteria. Sci Signal. 2012 Jan 24; 5(208):ra7.
          View in: PubMed
        16. Griffin JE, Gawronski JD, Dejesus MA, Ioerger TR, Akerley BJ, Sassetti CM. High-resolution phenotypic profiling defines genes essential for mycobacterial growth and cholesterol catabolism. PLoS Pathog. 2011 Sep; 7(9):e1002251.
          View in: PubMed
        17. Baek SH, Li AH, Sassetti CM. Metabolic regulation of mycobacterial growth and antibiotic sensitivity. PLoS Biol. 2011 May; 9(5):e1001065.
          View in: PubMed
        18. Lee J, Repasy T, Papavinasasundaram K, Sassetti C, Kornfeld H. Mycobacterium tuberculosis induces an atypical cell death mode to escape from infected macrophages. PLoS One. 2011; 6(3):e18367.
          View in: PubMed
        19. Wei JR, Krishnamoorthy V, Murphy K, Kim JH, Schnappinger D, Alber T, Sassetti CM, Rhee KY, Rubin EJ. Depletion of antibiotic targets has widely varying effects on growth. Proc Natl Acad Sci U S A. 2011 Mar 8; 108(10):4176-81.
          View in: PubMed
        20. Sassetti CM, Rubin EJ. Relics of selection in the mycobacterial genome. Nat Genet. 2010 Jun; 42(6):476-8.
          View in: PubMed
        21. Ioerger TR, Feng Y, Ganesula K, Chen X, Dobos KM, Fortune S, Jacobs WR, Mizrahi V, Parish T, Rubin E, Sassetti C, Sacchettini JC. Variation among genome sequences of H37Rv strains of Mycobacterium tuberculosis from multiple laboratories. J Bacteriol. 2010 Jul; 192(14):3645-53.
          View in: PubMed
        22. Murry JP, Pandey AK, Sassetti CM, Rubin EJ. Phthiocerol dimycocerosate transport is required for resisting interferon-gamma-independent immunity. J Infect Dis. 2009 Sep 1; 200(5):774-82.
          View in: PubMed
        23. Coulombe F, Divangahi M, Veyrier F, de Léséleuc L, Gleason JL, Yang Y, Kelliher MA, Pandey AK, Sassetti CM, Reed MB, Behr MA. Increased NOD2-mediated recognition of N-glycolyl muramyl dipeptide. J Exp Med. 2009 Aug 3; 206(8):1709-16.
          View in: PubMed
        24. Pandey AK, Yang Y, Jiang Z, Fortune SM, Coulombe F, Behr MA, Fitzgerald KA, Sassetti CM, Kelliher MA. NOD2, RIP2 and IRF5 play a critical role in the type I interferon response to Mycobacterium tuberculosis. PLoS Pathog. 2009 Jul; 5(7):e1000500.
          View in: PubMed
        25. Chang JC, Miner MD, Pandey AK, Gill WP, Harik NS, Sassetti CM, Sherman DR. igr Genes and Mycobacterium tuberculosis cholesterol metabolism. J Bacteriol. 2009 Aug; 191(16):5232-9.
          View in: PubMed
        26. Miner MD, Chang JC, Pandey AK, Sassetti CM, Sherman DR. Role of cholesterol in Mycobacterium tuberculosis infection. Indian J Exp Biol. 2009 Jun; 47(6):407-11.
          View in: PubMed
        27. Sassetti CM. Inducible expression systems for mycobacteria. Methods Mol Biol. 2009; 465:255-64.
          View in: PubMed
        28. Pandey AK, Raman S, Proff R, Joshi S, Kang CM, Rubin EJ, Husson RN, Sassetti CM. Nitrile-inducible gene expression in mycobacteria. Tuberculosis (Edinb). 2009 Jan; 89(1):12-6.
          View in: PubMed
        29. Pandey AK, Sassetti CM. Mycobacterial persistence requires the utilization of host cholesterol. Proc Natl Acad Sci U S A. 2008 Mar 18; 105(11):4376-80.
          View in: PubMed
        30. Murry JP, Sassetti CM, Lane JM, Xie Z, Rubin EJ. Transposon site hybridization in Mycobacterium tuberculosis. Methods Mol Biol. 2008; 416:45-59.
          View in: PubMed
        31. Yang Y, Yin C, Pandey A, Abbott D, Sassetti C, Kelliher MA. NOD2 pathway activation by MDP or Mycobacterium tuberculosis infection involves the stable polyubiquitination of Rip2. J Biol Chem. 2007 Dec 14; 282(50):36223-9.
          View in: PubMed
        32. Sassetti CM, Rubin EJ. The open book of infectious diseases. Nat Med. 2007 Mar; 13(3):279-80.
          View in: PubMed
        33. Joshi SM, Pandey AK, Capite N, Fortune SM, Rubin EJ, Sassetti CM. Characterization of mycobacterial virulence genes through genetic interaction mapping. Proc Natl Acad Sci U S A. 2006 Aug 1; 103(31):11760-5.
          View in: PubMed
        34. Murry J, Sassetti CM, Moreira J, Lane J, Rubin EJ. A new site-specific integration system for mycobacteria. Tuberculosis (Edinb). 2005 Sep-Nov; 85(5-6):317-23.
          View in: PubMed
        35. Rengarajan J, Sassetti CM, Naroditskaya V, Sloutsky A, Bloom BR, Rubin EJ. The folate pathway is a target for resistance to the drug para-aminosalicylic acid (PAS) in mycobacteria. Mol Microbiol. 2004 Jul; 53(1):275-82.
          View in: PubMed
        36. Sassetti CM, Rubin EJ. Genetic requirements for mycobacterial survival during infection. Proc Natl Acad Sci U S A. 2003 Oct 28; 100(22):12989-94.
          View in: PubMed
        37. Fieger CB, Sassetti CM, Rosen SD. Endoglycan, a member of the CD34 family, functions as an L-selectin ligand through modification with tyrosine sulfation and sialyl Lewis x. J Biol Chem. 2003 Jul 25; 278(30):27390-8.
          View in: PubMed
        38. Sassetti CM, Boyd DH, Rubin EJ. Genes required for mycobacterial growth defined by high density mutagenesis. Mol Microbiol. 2003 Apr; 48(1):77-84.
          View in: PubMed
        39. Sassetti C, Rubin EJ. Genomic analyses of microbial virulence. Curr Opin Microbiol. 2002 Feb; 5(1):27-32.
          View in: PubMed
        For assistance with using Profiles, please refer to the online tutorials or contact UMMS Help Desk or call 508-856-8643.
        Christopher's Networks
        Click the "See All" links for more information and interactive visualizations!
        Concepts
        _
        Co-Authors
        _
        Similar People
        _
        Same Department
        Physical Neighbors
        _

        This is an official Page/Publication of the University of Massachusetts Worcester Campus
        Office of the Vice Provost for Research, 55 Lake Ave North, Worcester, Massachusetts 01655
        Questions or Comments? Email: publicaffairs@umassmed.edu Phone: 508-856-1572