Tuberculosis (TB) remains a major human public health threat, killing approximately 1.5 million people every year. The emergence of drug-resistant strains of M. tuberculosis (MTB) and the lack of an effective vaccine are major challenges for TB control and eradication.
One of the key barriers to the development of new TB drugs and vaccines is our incomplete understanding of how MTB regulates the host immune response. MTB infects mononuclear phagocytes and has evolved many strategies to evade the immune response and to survive and persist in the host. MTB survival can be seen as a two-stage process: early survival in a non-activated macrophage and late survival in an IFN-γ-activated macrophage. In the first stage, MTB confronts the innate ability of the host macrophage to kill through iNOS, reactive oxygen species, lytic enzymes and presumably by limiting access to nutrients. The second stage of MTB survival (latency) occurs in 90% of infected individuals and depends on the activation of T cells that, through IFN-γ, activate macrophages to increase its bacteriostatic/ bactericidal functions.
Our lab interest is to clearly define the molecular mechanisms by which MTB regulates both infected phagocytes and T cells. The lab is developing a novel genome-wide approach using short hairpin RNAs to identify host factors that are required for MTB to survive in macrophages. We are particularly interested in host proteins that have potential as drug targets. In addition, we are identifying and characterizing in vitro and in vivo the role of MTB molecules that, by escaping the macrophage, gain access to and interact directly with T cells. We are studying the role of mycobacterial TLR2 ligands and cell wall glycolipids in direct regulation of CD4+ T cell activation using an MTB aerosol infection mouse model and adoptive transfer of MTB antigen-specific transgenic T cells.
LAB MEMBERS: Xuedong Ding, A. Faisal Karim, Qing Li and Scott M. Reba
Qing Li, Xuedong Ding, Jeremy J. Thomas, Clifford V. Harding, Nicole D. Pecora, Assem G. Ziady, Samuel Shank, W. Henry Boom, Christina L. Lancioni and Roxana E. Rojas. 2012. Rv2468c, a novel Mycobacterium tuberculosis protein that co-stimulates human CD4+ T cells through VLA-5. J. Leukoc. Biol. 2012 Feb; 91(2): 311-2. PMCID: PMC3290430 [Available on 2013/2/1]
Robert N. Mahon, Obondo J Sande; Roxana E Rojas, Alan D Levine, Clifford V Harding, Henry Boom. (2012). Mycobacterium tuberculosis ManLAM inhibits T-cell-receptor signaling by interference with ZAP-70, Lck and LAT phosphorylation. Cell. Immunol. 275(1-2):98-105. PMCID: PMC3352599 [Available on 2013/3/14]
Christina L. Lancioni, Qing Li, Jeremy J. Thomas, Xuedong Ding, Bonnie Thiel, Michael G. Drage, Nicole D. Pecora, Assem G. Ziady, Samuel Shank, Clifford V. Harding, W. Henry Boom and Roxana E. Rojas. (2011). Mycobacterium tuberculosis lipoproteins directly regulate human memory CD4+ T cell activation via TLR2/1. Infection and Immunity. 79 (2): 663-673. PMCID: PMC3028837.
Drage, M.G., Tsai, H.-C., Pecora, N.D., Cheng, T.-Y., Arida, A.R., Shukla, S., Rojas, R.E., Moody, D.B., Boom, W.H., Sacchettini, J.C., and Harding, C.V. (2010). Mycobacterium tuberculosis lipoprotein LprG (Rv1411c) binds triacylated glycolipid agonists of Toll-like receptor 2. Nature Struct. Mol. Biol. 17: 1088-1095. PMCID: PMC2933325.
Lancioni, C. L., J. J. Thomas, and R. E. Rojas. (2009). Activation requirements and responses to TLR ligands in human CD4+ T cells: comparison of two T cell isolation techniques. J. Immunol. Methods, 344(1):15-25. PMCID. PMC2674982.
Mahon R. N., Rojas R. E., Fulton S. A., Franko J., Harding C. V. and Boom W. H. (2009). Mycobacterium tuberculosis cell wall glycolipids directly inhibit CD4+ T-cell activation by interfering with proximal T-cell-receptor signaling. Infect. Immun., 77(10): 4574-83. PMCID: PMC2747961.