eBriefing

Tuberculosis Update

Tuberculosis Update
Reported by
Marilynn Larkin

Posted January 12, 2010

Overview

Tuberculosis (TB) claims about three million lives annually. In an effort to create more targeted therapies and, ultimately, vaccines, researchers are delving more deeply into the mechanistic aspects of the disease, using innovative approaches to tease out the key players at the cellular level that orchestrate the body's response to this global killer. Some of these promising approaches were discussed at a TB update at the Academy on June 6, 2006.

JoAnne Flynn introduced a relatively new model of TB—the Macaque monkey—and showed how this model, because of its similarity to human disease, facilitates the study of latent infection and reactivation.

Padmini Salgame offered insights into the differential responses of dendritic cells and macrophages to TB infection.

Anne Goldfeld described her team's work in Cambodia, where they are studying the mechanisms that underlie the interactions between Mycobacterium tuberculosis and the immune system, as well as the dynamics of TB and human immunodeficiency virus (HIV) co-infection.

Use the tabs above to find a meeting report and multimedia from this event.

Web Sites

The Bill & Melinda Gates Foundation: Tuberculosis
This site features articles and videos highlighting global health issues concerning tuberculosis. Videos and articles focus on current progress and directions for further research.

Centers for Disease Control and Prevention: Division of Tuberculosis Elimination
The CDC offers tuberculosis statistics, resources for education and training, and guidelines for treatment and prevention of the disease. Also available are the TB Notes Newsletter from the TB Trials Consortium, a report entitled Controlling Tuberculosis in the United States (PDF, 1.1 MB), and Guidelines for the Investigation of Contacts of Persons with Infectious Tuberculosis (PDF, 0.5 MB).

Global Alliance for TB Drug Development
One of the goals of this nonprofit organization is to accelerate "the discovery and development of faster-acting and affordable drugs to fight tuberculosis." The site offers news about clinical trials.

NIAID Fact Sheet on Tuberculosis
Contains general information about the spread, prevention, and treatment of tuberculosis.

World Health Organization: Tuberculosis
WHO provides fact sheets, a database, and information about treatment and prevention of tuberculosis in populations around the world.


Journal Articles

A Macaque Model of Tuberculosis: What Can We Learn?

Algood, H. M., J. Chan & J. L. Flynn. 2003. Chemokines and tuberculosis. Cytokine Growth Factor Rev. 14: 467-477.

Algood, H. M. & J. L. Flynn. 2004. CCR5-deficient mice control Mycobacterium tuberculosis infection despite increased pulmonary lymphocytic infiltration. J. Immunol. 173: 3287-3296. FULL TEXT

Algood, H. M., P. L. Lin & J. L. Flynn. 2005. Tumor necrosis factor and chemokine interactions in the formation and maintenance of granulomas in tuberculosis. Clin. Infect. Dis. 41 suppl 3: S189-S193. FULL TEXT

Algood, H. M., P. L. Lin, D. Yankura, et al. 2004. TNF influences chemokine expression of macrophages in vitro and that of CD11b+ cells in vivo during Mycobacterium tuberculosis infection. J. Immunol. 172: 6846-6857. FULL TEXT

Capuano, S. V., III, D. A. Croix, S. Pawar , et al. 2003. Experimental Mycobacterium tuberculosis infection of cynomolgus macaques closely resembles the various manifestations of human M. tuberculosis infection. Infect. Immun. 71: 5831-5844. FULL TEXT

Fuller C. L., J. L. Flynn & T. A. Reinhart. 2003. In situ study of abundant expression of proinflammatory chemokines and cytokines in pulmonary granulomas that develop in cynomolgus macaques experimentally infected with Mycobacterium tuberculosis. Infect. Immun. 71: 7023-7034. FULL TEXT

Flynn, J. L. 2006. Lessons from experimental Mycobacterium tuberculosis infections. Microbes. Infect. 8: 1179-1188.

Flynn, J. L. & J. Chan. 2005. What's good for the host is good for the bug. Trends Microbiol. 13: 98-102.

Flynn J. L. & J. Chan. 2003. Immune evasion by Mycobacterium tuberculosis: living with the enemy. Curr. Opin. Immunol. 15: 450-455.

Flynn, J. L. 2004. Immunology of tuberculosis and implications in vaccine development. Tuberculosis (Edinb.) 84: 93-101.

Flynn, J. L. 2004. Mutual attraction: does it benefit the host or the bug? Nat. Immunol. 5: 778-779.

Lazarevic V., A. J. Myers, C. A. Scanga, J. L. Flynn. 2003. CD40, but not CD40L, is required for the optimal priming of T cells and control of aerosol M. tuberculosis infection. Immunity 19: 823-835.

Lazarevic, V., D. Nolt & J. L. Flynn. 2005. Long-term control of Mycobacterium tuberculosis infection is mediated by dynamic immune responses. J. Immunol. 175: 1107-1117.

Lazarevic V., D. J. Yankura, S. J. DiVito & J. L. Flynn. 2005. Induction of Mycobacterium tuberculosis-specific primary and secondary T-cell responses in interleukin-15-deficient mice. Infect. Immun. 73: 2910-2922. FULL TEXT

Lin, P. L., S. Pawar, A. Myers, et al. 2006. Early events in Mycobacterium tuberculosis infection in cynomolgus macaques. Infect. Immun. 74: 3790-3803.

Marino, S., S. Pawar, C. L. Fuller, et al. 2004. Dendritic cell trafficking and antigen presentation in the human immune response to Mycobacterium tuberculosis. J. Immunol. 173: 494-506. FULL TEXT

Myers, A. J., B. Eilertson, S. A. Fulton, et al. 2005. The purinergic P2X7 receptor is not required for control of pulmonary Mycobacterium tuberculosis infection. Infect. Immun. 73: 3192-3195. FULL TEXT

Nolt, D. & J. L. Flynn. 2004. Interleukin-12 therapy reduces the number of immune cells and pathology in lungs of mice infected with Mycobacterium tuberculosis. Infect. Immun. 72: 2976-2988. FULL TEXT

Sud, D., C. Bigbee, J. L. Flynn & D. E. Kirschner. 2006. Contribution of CD8+ T cells to control of Mycobacterium tuberculosis infection. J. Immunol. 176: 4296-4314.

Tufariello, J. M., J. Chan & J. L. Flynn. 2003. Latent tuberculosis: mechanisms of host and bacillus that contribute to persistent infection. Lancet Infect. Dis. 3: 578-590.

A Tale of Two Cells: Interaction of M. tuberculosis with Dendritic Cells and Macrophages

Bagenstose, L. M., R. Class, P. Salgame & M. Monestier. 2002. B7-1 and B7-2 co-stimulatory molecules are required for mercury-induced autoimmunity. Clin. Exp. Immunol. 127: 12-19. FULL TEXT

Bhatt, K., S. P. Hickman & P. Salgame. 2004. Cutting edge: a new approach to modeling early lung immunity in murine tuberculosis. J. Immunol. 172: 2748-2751. FULL TEXT

Hanlon, A., S. Jang, P. Salgame. 2005. Cbl-b differentially regulates activation-induced apoptosis in T helper 1 and T helper 2 cells. Immunology 116: 507-512.

Hanlon, A. M., S. Jang & P. Salgame. 2002. Signaling from cytokine receptors that affect Th1 responses. Front. Biosci. 7: d1247-d1254.

Hickman, S. P., J. Chan & P. Salgame. 2002. Mycobacterium tuberculosis induces differential cytokine production from dendritic cells and macrophages with divergent effects on naive T cell polarization. J. Immunol. 168: 4636-4642. FULL TEXT

Hu, C., T. Mayadas-Norton, K. Tanaka, et al. 2000. Mycobacterium tuberculosis infection in complement receptor 3-deficient mice. J. Immunol. 165: 2596-2602. FULL TEXT

Jang, S., P. H. Krammer & P. Salgame. 2003. Lack of proapoptotic activity of soluble CD95 ligand is due to its failure to induce CD95 oligomers. J. Interferon Cytokine Res. 23: 441-447.

Jang, S., S. Uematsu, S. Akira & P. Salgame. 2004. IL-6 and IL-10 induction from dendritic cells in response to Mycobacterium tuberculosis is predominantly dependent on TLR2-mediated recognition. J. Immunol. 173: 3392-3397. FULL TEXT

Salgame, P. 2005. Host innate and Th1 responses and the bacterial factors that control Mycobacterium tuberculosis infection. Curr. Opin. Immunol. 17: 374-380.

Varadhachary, A. S., M. Edidin, A. M. Hanlon, et al. 2001. Phosphatidylinositol 3′-kinase blocks CD95 aggregation and caspase-8 cleavage at the death-inducing signaling complex by modulating lateral diffusion of CD95. J. Immunol. 166: 6564-6569. FULL TEXT

Varadhachary, A. S., M. Monestier & P. Salgame. 2001. Reciprocal induction of IL-10 and IL-12 from macrophages by low-density lipoprotein and its oxidized forms. Cell. Immunol. 213: 45-51.

Zhu, G., H. Xiao, V. P. Mohan, et al. 2003. Gene expression in the tuberculous granuloma: analysis by laser capture microdissection and real-time PCR. Cell. Microbiol. 5: 445-453. FULL TEXT

Mechanisms of TB Host Pathogen Interactions: From Community-Based Care to the Bench

Baena, A., J. Y. Leung, A. D. Sullivan, et al. 2002. TNF-α promoter single nucleotide polymorphisms are markers of human ancestry. Genes Immun. 3: 482-487.

Barthel, R. & A. E. Goldfeld. 2003. T cell-specific expression of the human TNF-α gene involves a functional and highly conserved chromatin signature in intron 3. J. Immunol. 171: 3612-3619. FULL TEXT

Barthel, R., A. V. Tsytsykova & A. K. Barczak. 2003. Regulation of tumor necrosis factor α gene expression by mycobacteria involves the assembly of a unique enhanceosome dependent on the coactivator proteins CBP/p300. Mol. Cell Biol. 23: 526-533. FULL TEXT

Delgado, J. C., A. Baena, S. Thim & A. E. Goldfeld. 2006. Aspartic acid homozygosity at codon 57 of HLA-DQ β is associated with susceptibility to pulmonary tuberculosis in Cambodia. J. Immunol. 176: 1090-1097.

Delgado, J. C., A. Baena, S. Thim & A. E. Goldfeld. 2002. Ethnic-specific genetic associations with pulmonary tuberculosis. J. Infect. Dis. 186: 1463-1468. FULL TEXT

Delgado, J. C., E. Y. Tsai, S. Thim, et al. 2002. Antigen-specific and persistent tuberculin anergy in a cohort of pulmonary tuberculosis patients from rural Cambodia. Proc. Natl. Acad. Sci. USA 99: 7576-7581. FULL TEXT

Delgado, J. C., J. Quinones-Berrocal, S. Thim, et al. 2004. Diagnostic and clinical implications of response to tuberculin in two ethnically distinct populations from Peru and Cambodia. Int. J. Tuberc. Lung Dis. 8: 982-987.

Delgado, J. C., J. Y. Leung, A. Baena, et al. 2003. The -1030/-862-linked TNF promoter single-nucleotide polymorphisms are associated with the inability to control HIV-1 viremia. Immunogenetics 55: 497-501.

Esensten, J. H., A. V. Tsytsykova, C. Lopez-Rodriguez, et al. 2005. NFAT5 binds to the TNF promoter distinctly from NFATp, c, 3 and 4, and activates TNF transcription during hypertonic stress alone. Nucleic Acids Res. 33: 3845-3854. FULL TEXT

Flores-Villanueva, P. O., E. J. Yunis, J. C. Delgado, et al. 2001. Control of HIV-1 viremia and protection from AIDS are associated with HLA-Bw4 homozygosity. Proc. Natl. Acad. Sci. USA 98: 5140-5145. FULL TEXT

Goldfeld, A. E. 2004. Genetic susceptibility to pulmonary tuberculosis in Cambodia. Tuberculosis (Edinb.) 84: 76-81.

Goldfeld, A. E., J. Y. Leung, S. A. Sawyer & D. L. Hartl. 2000. Post-genomics and the neutral theory: variation and conservation in the tumor necrosis factor-α promoter. Gene 261: 19-25.

O'Garra, A., P. L. Vieira, P. Vieira & A. E. Goldfeld. 2004. IL-10-producing and naturally occurring CD4+ Tregs: limiting collateral damage. J. Clin. Invest. 114: 1372-1378. FULL TEXT

Ranjbar, S., N. Ly, S. Thim, et al. 2004. Mycobacterium tuberculosis recall antigens suppress HIV-1 replication in anergic donor cells via CD8+ T cell expansion and increased IL-10 levels. J. Immunol. 172: 1953-1959. FULL TEXT

Ranjbar, S., R. Rajsbaum & A. E. Goldfeld. 2006. Transactivator of transcription from HIV type 1 subtype E selectively inhibits TNF gene expression via interference with chromatin remodeling of the TNF locus. J. Immunol. 176: 4182-4190.

Saraiva, M., J. R. Christensen, A. V. Tsytsykova, et al. 2005. Identification of a macrophage-specific chromatin signature in the IL-10 locus. J. Immunol. 175: 1041-1046.

Thim, S., S. Sath, M. Sina, et al. 2004. A community-based tuberculosis program in Cambodia. JAMA 292: 566-568.

Tsytsykova, A. V. & A. E. Goldfeld. 2002. Inducer-specific enhanceosome formation controls tumor necrosis factor alpha gene expression in T lymphocytes. Mol. Cell Biol. 22: 2620-2631. FULL TEXT

Tsytsykova, A. V. & A. E. Goldfeld. 2000. Nuclear factor of activated T cells transcription factor NFATp controls superantigen-induced lethal shock. J. Exp. Med. 192: 581-586. FULL TEXT

Speakers

JoAnne L. Flynn, PhD

University of Pittsburgh School of Medicine
email | web site | publications

JoAnne Flynn received her PhD in microbiology and immunology from the University of California, Berkeley in 1987. Her PhD thesis involved a study of a virulence factor, alginate, produced by Pseudomonas aeruginosa isolates from cystic fibrosis patients. In 1987, Flynn moved to La Jolla to do postdoctoral research in the lab of Maggie So at the Scripps Research Institute, developing salmonella as a vaccine delivery vehicle. From 1990–1993, she was a Howard Hughes postdoctoral fellow in the laboratory of Barry Bloom at Albert Einstein College of Medicine. This is where she began her work on tuberculosis. In 1994, Flynn joined the faculty of the Department of Microbiolgy and Immunology, University of Pittsburgh School of Medicine. She is now a professor in that department, with secondary appointments in immunology, medicine, and pediatrics.

Padmini Salgame, PhD

UMDNJ-New Jersey Medical School
email | web site | publications

Padmini Salgame holds the position of tenured professor in the Department of Medicine, Division of Infectious Diseases and Center for Emerging Pathogens at UMDNJ-New Jersey Medical School. Salgame obtained her doctoral degree from the University of Bombay, India. Postdoctoral studies were undertaken at University College London, and at the Albert Einstein College of Medicine, NY. She launched her career as an independent investigator at Temple University where she attained the rank of associate professor. In 2003, she was recruited to UMDNJ as professor of medicine, where she directs an experimental research laboratory studying host immunity to tuberculosis.

Anne E. Goldfeld, MD

CBR Institute for Biomedical Research
email | web site | publications

Anne Goldfeld attended Brown University and the University of California, Berkeley, where she earned a bachelor's degree in zoology. After receiving her MD from Albert Einstein College of Medicine, she completed a residency in internal medicine and a clinical fellowship in infectious disease at the Massachusetts General Hospital, followed by postdoctoral research training at Harvard University and the Dana-Farber Cancer Institute.

Goldfeld has been a devoted advocate for health and human rights particularly as related to refugees working in many postconflict settings around the world. In 1994, she cofounded the Cambodian Health Committee with Sok Thim and has pioneered community-based TB treatment and more recently AIDS treatment strategies in southeastern Cambodia that integrate basic scientific discovery with operational models.

Goldfeld is an investigator at the CBR Institute for Biomedical Research, an associate professor of medicine at Harvard Medical School, associate professor of immunology and infectious disease at the Harvard School of Public Health, and a member of the Infectious Disease Division at Brigham & Women's Hospital. Her lab focuses on basic mechanisms of gene transcription and on immunopathogenic factors involved in TB and AIDS pathogenesis.


Marilynn Larkin
Marilynn Larkin is a medical editor, journalist, and videographer based in New York City. Her work has frequently appeared in, among others, The Lancet, The Lancet Infectious Diseases, and Reuters Health's professional newswire. She is currently head of publications for The Society for Biomolecular Screening.

Ms. Larkin has served as editor of clinical publications for neurologists, anesthesiologists, HIV providers, and long-term care professionals. She also developed physician/patient education videos and continuing medical education symposia for several medical communications companies.

Prior to her work for physician audiences, she covered health, nutrition, fitness, psychology, and travel for women's and general interest magazines. She is also author of five medical books for general readers, and of Reporting on Health Risk, a handbook for journalists.

In 2004, Ms. Larkin started her own fitness consulting company (www.mlarkinfitness.com), and developed a class, Posture-cize, that helps people improve their posture, increase productivity, and reduce injury.