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Public Health Research Institute Center
UMDNJ - New Jersey Medical School
225 Warren Street
Newark, New Jersey 07103
Phone: (973) 854-3260
e-mail: smithis@umdnj.edu
 Research Summary
The Genetics of Mycobacterium tuberculosis Virulence
Dr. Smith and his laboratory has been studying the genetics of Mycobacterium tuberculosis virulence to better understand the processes by which the bacterium causes tuberculosis. They are using two major approaches. The first is a novel genetic screen or "promoter trap" that selects for M. tuberculosis genes that are more active during infection. They have found approximately 50 M. tuberculosis genes that are more active when the bacterium infects macrophages - the cells in the human body that protect against infection - and approximately 60 others in the lungs of infected mice. Among the genes they identified are several that are involved in fatty acid metabolism. The lab is currently making M. tuberculosis strains with mutations in some of these genes to ascertain their role in virulence, as well as isolating more genes by the promoter trap technique.
Their second approach uses the published M. tuberculosis genome database to identify and characterize proteins that are expected to be important for virulence based on their similarity to known virulence determinants in other bacterial pathogens. They have studied three main classes of bacterial regulatory proteins, ie sigma factors, metalloregulators and two-component systems and found that inactivation of genes encoding some of these regulatory proteins reduces their virulence in human and mouse macrophages and in mice.
Dr. Smith and the members of his laboratory are now studying which genes controlled by the regulatory proteins are essential for M. tuberculosis virulence, using modern technology such as molecular beacons and DNA arrays, to identify those genes controlled by the 2 regulators during infections. Currently, the group is using some of the targets they have identified to develop new strategies, eg vaccines, for the treatment of tuberculosis.
Selected TB bibliography (Since 1995)
Yang X, Gao J, Smith I, Dubnau E, Sampson NS (2011) Cholesterol is not an essential source of nutrition for Mycobacterium tuberculosis during infection. J Bacteriol 193: 1473-1476. PMI: 21257778
Hernandez Pando R, Aguilar LD, Smith I, Manganelli R (2011) Immunogenicity and protection induced by a Mycobacterium tuberculosis sigE mutant in a BALB/c mouse model of progressive pulmonary tuberculosis. Infect Immun 78: 3168-3176. PMI: 20457786
Ryndak MB, Wang S, Smith I, Rodriguez GM (2010) The Mycobacterium tuberculosis high-affinity iron importer, IrtA, contains an FAD-binding domain. J Bacteriol 192: 861-869. PMI: 19948799
Nesbitt NM, Yang X, Fontan P, Kolesnikova I, Smith I, Sampson NS, Dubnau E (2010) A thiolase of Mycobacterium tuberculosis is required for virulence and production of androstenedione and androstadienedione from cholesterol. Infect Immun 78: 275-282. PMI: 19822655
Yang X, Nesbitt NM, Dubnau E, Smith I, Sampson NS (2009) Cholesterol metabolism increases the metabolic pool of propionate in Mycobacterium tuberculosis. Biochemistry 48: 3819-3821. PMI: 19364125
Fontan PA, Voskuil MI, Gomez M, Tan D, Pardini M, Manganelli R, Fattorini L, Schoolnik GK, Smith I (2009) The Mycobacterium tuberculosis sigma factor sigmaB is required for full response to cell envelope stress and hypoxia in vitro, but it is dispensable for in vivo growth. J Bacteriol 191: 5628-5633. PMI: 19592585
Ryndak M, Wang S, Smith I (2008) PhoP, a key player in Mycobacterium tuberculosis virulence. Trends Microbiol 16: 528-534. PMI: 18835713
Ryndak M, Wang S, Smith I (2008) PhoP, a key player in Mycobacterium tuberculosis virulence. Trends Microbiol 16: 528-534. PMI: 18835713
Rao PK, Rodriguez GM, Smith I, Li Q (2008) Protein dynamics in iron-starved Mycobacterium tuberculosis revealed by turnover and abundance measurement using hybrid-linear ion trap-Fourier transform mass spectrometry. Anal Chem 80: 6860-6869. PMI: 18690695
Fontan PA, Aris V, Alvarez ME, Ghanny S, Cheng J, Soteropoulos P, Trevani A, Pine R, Smith I (2008) Mycobacterium tuberculosis sigma factor E regulon modulates the host inflammatory response. J Infect Dis 198: 877-885. PMI: 18657035
Fontan P, Aris V, Ghanny S, Soteropoulos P, Smith I (2008) Global transcriptional profile of Mycobacterium tuberculosis during THP-1 human macrophage infection. Infect Immun 76: 717-725. PMI: 18070897
Yang X, Dubnau E, Smith I, Sampson NS (2007) Rv1106c from Mycobacterium tuberculosis is a 3beta-hydroxysteroid dehydrogenase. Biochemistry 46: 9058-9067. PMI: 17630785
Williams DL, Pittman TL, Deshotel M, Oby-Robinson S, Smith I, Husson R (2007) Molecular basis of the defective heat stress response in Mycobacterium leprae. J Bacteriol 189: 8818-8827. PMI: 17933896
Wang S, Engohang-Ndong J, Smith I (2007) Structure of the DNA-binding domain of the response regulator PhoP from Mycobacterium tuberculosis. Biochemistry 46: 14751-14761. PMI: 18052041
Rehren G, Walters S, Fontan P, Smith I, Zarraga AM (2007) Differential gene expression between Mycobacterium bovis and Mycobacterium tuberculosis. Tuberculosis (Edinb) 87: 347-359. PMI: 17433778
Raviglione MC, Smith IM (2007) XDR tuberculosis--implications for global public health. N Engl J Med 356: 656-659. PMI: 17301295
Maciag A, Dainese E, Rodriguez GM, Milano A, Provvedi R, Pasca MR, Smith I, Palu G, Riccardi G, Manganelli R (2007) Global analysis of the Mycobacterium tuberculosis Zur (FurB) regulon. J Bacteriol 189: 730-740. PMI: 17098899
Walters SB, Dubnau E, Kolesnikova I, Laval F, Daffe M, Smith I (2006) The Mycobacterium tuberculosis PhoPR two-component system regulates genes essential for virulence and complex lipid biosynthesis. Mol Microbiol 60: 312-330. PMI: 16573683
Rodriguez GM, Smith I (2006) Identification of an ABC transporter required for iron acquisition and virulence in Mycobacterium tuberculosis. J Bacteriol 188: 424-430. PMI: 16385031
Giacomini E, Sotolongo A, Iona E, Severa M, Remoli ME, Gafa V, Lande R, Fattorini L, Smith I, Manganelli R, Coccia EM (2006) Infection of human dendritic cells with a Mycobacterium tuberculosis sigE mutant stimulates production of high levels of interleukin-10 but low levels of CXCL10: impact on the T-cell response. Infect Immun 74: 3296-3304. PMI: 16714557
Dainese E, Rodrigue S, Delogu G, Provvedi R, Laflamme L, Brzezinski R, Fadda G, Smith I, Gaudreau L, Palu G, Manganelli R (2006) Posttranslational regulation of Mycobacterium tuberculosis extracytoplasmic-function sigma factor sigma L and roles in virulence and in global regulation of gene expression. Infect Immun 74: 2457-2461. PMI: 16552079
Smith I, Nathan C, Peavy HH (2005) Progress and new directions in genetics of tuberculosis: an NHLBI working group report. Am J Respir Crit Care Med 172: 1491-1496. PMI: 16192449
Mendelson M, Walters S, Smith I, Kaplan G (2005) Strain-specific mycobacterial lipids and the stimulation of protective immunity to tuberculosis. Tuberculosis (Edinb) 85: 407-413. PMI: 16249121
Dubnau E, Chan J, Mohan VP, Smith I (2005) responses of mycobacterium tuberculosis to growth in the mouse lung. Infect Immun 73: 3754-3757. PMI: 15908407
Manganelli R, Provvedi R, Rodrigue S, Beaucher J, Gaudreau L, Smith I (2004) Sigma factors and global gene regulation in Mycobacterium tuberculosis. J Bacteriol 186: 895-902. PMI: 14761983
Manganelli R, Fattorini L, Tan D, Iona E, Orefici G, Altavilla G, Cusatelli P, Smith I (2004) The extra cytoplasmic function sigma factor sigma(E) is essential for Mycobacterium tuberculosis virulence in mice. Infect Immun 72: 3038-3041. PMI: 15102817
Timm J, Post FA, Bekker LG, Walther GB, Wainwright HC, Manganelli R, Chan WT, Tsenova L, Gold B, Smith I, Kaplan G, McKinney JD (2003) Differential expression of iron-, carbon-, and oxygen-responsive mycobacterial genes in the lungs of chronically infected mice and tuberculosis patients. Proc Natl Acad Sci U S A 100: 14321-14326. PMI: 14623960
Smith I (2003) Mycobacterium tuberculosis pathogenesis and molecular determinants of virulence. Clin Microbiol Rev 16: 463-496. PMI: 12857778
Rodriguez GM, Smith I (2003) Mechanisms of iron regulation in mycobacteria: role in physiology and virulence. Mol Microbiol 47: 1485-1494. PMI: 12622807
Dubnau E, Smith I (2003) Mycobacterium tuberculosis gene expression in macrophages. Microbes Infect 5: 629-637. PMI: 12787739
Dubnau E, Smith I (2003) Mycobacterium tuberculosis gene expression in macrophages. Microbes Infect 5: 629-637. PMI: 12787739
Rodriguez GM, Voskuil MI, Gold B, Schoolnik GK, Smith I (2002) ideR, An essential gene in mycobacterium tuberculosis: role of IdeR in iron-dependent gene expression, iron metabolism, and oxidative stress response. Infect Immun 70: 3371-3381. PMI: 12065475
Manganelli R, Voskuil MI, Schoolnik GK, Dubnau E, Gomez M, Smith I (2002) Role of the extracytoplasmic-function sigma factor sigma(H) in Mycobacterium tuberculosis global gene expression. Mol Microbiol 45: 365-374. PMI: 12123450
Dubnau E, Fontan P, Manganelli R, Soares-Appel S, Smith I (2002) Mycobacterium tuberculosis genes induced during infection of human macrophages. Infect Immun 70: 2787-2795. PMI: 12010964
Manganelli R, Voskuil MI, Schoolnik GK, Smith I (2001) The Mycobacterium tuberculosis ECF sigma factor sigmaE: role in global gene expression and survival in macrophages. Mol Microbiol 41: 423-437. PMI: 11489128
Manganelli R, Tyagi S, Smith I (2001) Real Time PCR Using Molecular Beacons : A New Tool to Identify Point Mutations and to Analyze Gene Expression in Mycobacterium tuberculosis. Methods Mol Med 54: 295-310. PMI: 21341083
Gold B, Rodriguez GM, Marras SA, Pentecost M, Smith I (2001) The Mycobacterium tuberculosis IdeR is a dual functional regulator that controls transcription of genes involved in iron acquisition, iron storage and survival in macrophages. Mol Microbiol 42: 851-865. PMI: 11722747
Dubnau E, Chan J, Raynaud C, Mohan VP, Laneelle MA, Yu K, Quemard A, Smith I, Daffe M (2000) Oxygenated mycolic acids are necessary for virulence of Mycobacterium tuberculosis in mice. Mol Microbiol 36: 630-637. PMI: 10844652
Rodriguez GM, Gold B, Gomez M, Dussurget O, Smith I (1999) Identification and characterization of two divergently transcribed iron regulated genes in Mycobacterium tuberculosis. Tuber Lung Dis 79: 287-298. PMI: 10707257
Manganelli R, Dubnau E, Tyagi S, Kramer FR, Smith I (1999) Differential expression of 10 sigma factor genes in Mycobacterium tuberculosis. Mol Microbiol 31: 715-724. PMI: 10027986
Dussurget O, Timm J, Gomez M, Gold B, Yu S, Sabol SZ, Holmes RK, Jacobs WR, Jr., Smith I (1999) Transcriptional control of the iron-responsive fxbA gene by the mycobacterial regulator IdeR. J Bacteriol 181: 3402-3408. PMI: 10348851
Smith I, Dussurget O, Rodriguez GM, Timm J, Gomez M, Dubnau J, Gold B, Manganelli R (1998) Extra and intracellular expression of Mycobacterium tuberculosis genes. Tuber Lung Dis 79: 91-97. PMI: 10645446
Gomez M, Doukhan L, Nair G, Smith I (1998) sigA is an essential gene in Mycobacterium smegmatis. Mol Microbiol 29: 617-628. PMI: 9720877
Dussurget O, Smith I (1998) Interdependence of mycobacterial iron regulation, oxidative-stress response and isoniazid resistance. Trends Microbiol 6: 354-358. PMI: 9778728
Dussurget O, Rodriguez M, Smith I (1998) Protective role of the Mycobacterium smegmatis IdeR against reactive oxygen species and isoniazid toxicity. Tuber Lung Dis 79: 99-106. PMI: 10645447
Dubnau E, Marrakchi H, Smith I, Daffe M, Quemard A (1998) Mutations in the cmaB gene are responsible for the absence of methoxymycolic acid in Mycobacterium bovis BCG Pasteur. Mol Microbiol 29: 1526-1528. PMI: 9781890
Dussurget O, Rodriguez M, Smith I (1996) An ideR mutant of Mycobacterium smegmatis has derepressed siderophore production and an altered oxidative-stress response. Mol Microbiol 22: 535-544. PMI: 8939436
Schmitt MP, Predich M, Doukhan L, Smith I, Holmes RK (1995) Characterization of an iron-dependent regulatory protein (IdeR) of Mycobacterium tuberculosis as a functional homolog of the diphtheria toxin repressor (DtxR) from Corynebacterium diphtheriae. Infect Immun 63: 4284-4289. PMI: 7591059
Predich M, Doukhan L, Nair G, Smith I (1995) Characterization of RNA polymerase and two sigma-factor genes from Mycobacterium smegmatis. Mol Microbiol 15: 355-366. PMI: 7746156
Doukhan L, Predich M, Nair G, Dussurget O, Mandic-Mulec I, Cole ST, Smith DR, Smith I (1995) Genomic organization of the mycobacterial sigma gene cluster. Gene 165: 67-70. PMI: 7489918
C.V.
Education
City College of New York, New York City, B.A., 1955; Columbia University, New York City, M.A., 1957 (Developmental Biology), Ph.D., 1961 (Developmental Biology).
Research Experience
Sloan Kettering Institute for Cancer Research, Post Doc., 1961-1962; New York University School of Medicine (Dept. of Microbiology), Post Doc., 1962-1963; Albert Einstein College of Medicine, Post Doc, 1963-1968; Research Assistant Professor (Dept. of Pathology) 1964-1967; New York University School of Medicine (Dept. of Microbiology), Research Assistant Professor, 1967 - 1980, Research Professor, 1980 Ð2004, Adjunct Professor of Medicine 2004-present; University of Medicine and Dentistry, New Jersey Medical School, Professor (Dept. of Medicine); PHRI (Dept. Of Microbiology 1967-1993, TB Center 1994-Present), Associate, 1967-1973, Associate Member, 1973-1980, Member, 1980-present.
Professional Experience
N.I.H. Study Sections: Microbial Physiology & Genetics I, Member, 1986-1990, Prokaryotic Molecular biology, Member, 2006-2010; Member of Editorial Boards: Journal of Bacteriology, 1975-1993, Molecular Microbiology 1995-2009; Board of Directors, International Spores Conference, Inc., President, 1984-1988; Organizing & Program Committees, 10th Intl. Spores Conference, Chairman, 1988; Board of Directors, International Spores Conference, Inc., Member, 1980-1992; 1st, 2nd and 3rd N.Y.C. TB Conferences (1996, 1998. 2000), Organizer; Public Health Research Institute Symposia on Infectious Diseases, Newark, NJ, 2002-2009, Organizer; ASM Tuberculosis Meeting, April, 1998, Keystone, CO., session Chair and Speaker, 1998; 31st -36th US/Japan TB/Leprosy Research Conferences, Nagasaki, Cleveland, Osaka, San Francisco, Yokohama, New Orleans, 1996-2001, Invited Speaker; ASM General Meeting, Atlanta, Los Angeles, Washington, DC, session Chair, Speaker 1998, 2000, speaker 2003; Keystone TB meeting 2007, Co-organizer; Chairman, Division U (Mycobacteriology) American Society of Microbiology 2006-2007.
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