Immune Response to Tuberculosis
According to the World Health Organization, in 2005 around 9 million people developed active tuberculosis (TB) and at least 1.6 million people died of TB. The Stop TB Partnership and the United Nations have set a goal to reduce the annual death toll from TB to less than 1 million worldwide by 2015. The current global strategy for TB control is focused on reducing the spread of infection through massive vaccination campaigns with BCG and treatment of individuals with active disease using multi-drug combinations. However, there are many problems with these approaches, including the low efficiency of BCG, the dramatic increase in TB among HIV positive individuals and the emergence of drug resistant strains of Mycobacterium tuberculosis (Mtb).
A critical barrier to the development of better TB control strategies has been insufficient knowledge of how Mtb alters the host immune system to cause infection. Dr. Hmama’s team has been investigating the subcellular and molecular mechanisms of host/pathogen interactions over the last six years. Their efforts have revealed subtle strategies used by pathogenic mycobacteria to invade the macrophage and attenuate critical functions such as intracellular killing and stimulation of T cell mediated specific immune response. In vitro studies also revealed that the BCG vaccine mimics the effects of virulent mycobacteria, which explains its low efficacy in TB prevention.
Ongoing research in the Hmama lab builds on original and innovative projects that challenge existing TB prevention and treatment practices. Dr. Hmama’s laboratory is developing novel gene manipulation technologies to upgrade the current BCG vaccine in order to maximize the induction of protective TB immunity. Of equal importance to the vaccine project, a biology-based study of Mtb persistence has revealed important virulence factors that represent attractive drug targets that could be used for TB treatment.
Wong D, Bach H, Sun J, Hmama Z, Av-Gay Y. Mycobacterium tuberculosis protein tyrosine phosphatase (PtpA) excludes host vacuolar-H+-ATPase to inhibit phagosome acidification. Proc Natl Acad Sci U S A. 2011 Nov 29;108(48):19371-6.
Sun J, Wang X, Lau A, Liao TY, Bucci C, Hmama Z. Mycobacterial nucleoside diphosphate kinase blocks phagosome maturation in murine RAW 264.7 macrophages. PLoS One. 2010 Jan 19;5(1)
Chao J, Wong D, Zheng X, Poirier V, Bach H, Hmama Z, Av-Gay Y. Protein kinase and phosphatase signaling in Mycobacterium tuberculosis physiology and pathogenesis. Biochim Biophys Acta. 2010 Mar;1804(3):620-7.
Sun J, Lau A, Wang X, Liao TY, Zoubeidi A, Hmama Z. A broad-range of recombination cloning vectors in mycobacteria. Plasmid. 2009 Nov;62(3):158-65. Epub 2009 Jul 30.
Sun J, Deghmane AE, Bucci C, Hmama Z. Detection of activated Rab7 GTPase with an immobilized RILP probe. Methods Mol Biol. 2009;531:57-69.
Bach H, Papavinasasundaram KG, Wong D, Hmama Z, Av-Gay Y. Mycobacterium tuberculosis virulence is mediated by PtpA dephosphorylation of human vacuolar protein sorting 33B. Cell Host Microbe. 2008 May 15;3(5):316-22.
Sun J, Deghmane AE, Soualhine H, Hong T, Bucci C, Solodkin A, Hmama Z. Mycobacterium bovis BCG disrupts the interaction of Rab7 with RILP contributing to inhibition of phagosome maturation. J Leukoc Biol. 2007 Dec;82(6):1437-45.
Soualhine H, Deghmane AE, Sun J, Mak K, Talal A, Av-Gay Y, Hmama Z. Mycobacterium bovis bacillus Calmette-Guérin secreting active cathepsin S stimulates expression of mature MHC class II molecules and antigen presentation in human macrophages. J Immunol. 2007 Oct 15;179(8):5137-45.
Deghmane AE, Soualhine H, Bach H, Sendide K, Itoh S, Tam A, Noubir S, Talal A, Lo R, Toyoshima S, Av-Gay Y, Hmama Z. Lipoamide dehydrogenase mediates retention of coronin-1 on BCG vacuoles, leading to arrest in phagosome maturation. J Cell Sci. 2007 Aug 15;120(Pt 16):2796-806.