Associate Professor
Infectious Diseases
Research Sumary:

My research program is aimed at (1) elucidating the mechanisms of host-pathogen interactions, and then (2) applying that research to develop and investigate novel vaccine and therapy strategies to prevent and fight TB.  Over the last 6 year funding period the following research activities have advanced each of these goals:
One objective of my initial studies was to understand the mechanisms of phagosome maturation arrest, a major strategy used by pathogenic mycobacteria to survive within host cells.  We examined the effect of mycobacterial infection on the homeostasis of macrophage (MØ) endosomal system and demonstrated that lipoarabinomannan (LAM), a major surface glycolipid in pathogenic mycobacteria, alter the endocytic pathway via ?-adducin phosphorylation (Infect Immun, 2003, 71:5514).  We subsequently developed a novel FACS-based approach that allows more precise studies of phagosome biogenesis and used it to demonstrate that LAM markedly decreased phagosome maturation (J Cell Sci, 2004, 117: 2131).  Further investigations on the properties of LAM revealed that this bacterial ligand contributes largely in mycobacterial uptake by regulating a cross-talk between MØ surface receptors CD14, TLR2 and CR3 (J Immunol, 2005, 174: 4210).  Convinced with the possibility that mycobacteria might display other activities that block the normal development of its phagosome, we developed several cell biology and molecular approaches to provide clear evidence that pathogenic mycobacteria export the enzyme lipoamide dehydrogenase (LpdC) into the endosomal system, which then inhibits phagosome maturation.  LpdC was found to act by a mechanism dependent on cholesterol-mediated abnormal retention of the coat protein coronin-1 on the phagosomal membrane (J Cell Sci, 2007, 120:2796).  Furthermore, we observed the presence of discrete cholesterol binding domains (ChBD) unique to BCG and M. tuberculosis (Mtb) LpdC and absent in M. smegmatis ortholog and showed that these domains are essential for cholesterol-mediated coronin-1 retention on the phagosome (Manuscript in preparation).  In keeping with these findings, another study showed that BCG and Mtb, but not M. smegmatis, expresses anti-GTPase activity leading to functional deactivation of the phagosomal regulator Rab7 GTPase.  Thus, inactivated Rab7 (GDP bound form) failed to interact with the protein RILP (for Rab7-Interacting Lysosomal Protein), which is an essential Rab7 downstream effector required for transport of endosomes to lysosomes (J Leukoc Biol, In press).  Additionally, a collaborative work with Dr. Av-Gay’s laboratory on the modulation of MØ signaling by mycobacteria revealed that Mtb export within the MØ a phosphotyrosine phosphatase (PtpA) (Infect Immun, 2006, 74:6540) that contribute to phagosome maturation arrest by dephosphorylating an important regulator of membrane fusion, the cytosolic VPS33B (vacuolar protein sorting 33B) (Submitted manuscript).
Another important project developed in my laboratory is the study of the mechanism of MHC class II down modulation in macrophages infected with mycobacteria.  Thus we have shown that the vaccine BCG reproduced, at least partially, the inhibitory effect of Mtb, via intracellular alkalization, leading ultimately to a defect in class II molecules trafficking and maturational processing. (Infect Immun 2004, 72: 4200).  Further studies examined the nature of class II molecules that do reach the surface of BCG-infected cells and found a predominance of invariant (Ii) chain associated class II molecules.  This phenotype was due to inhibition of cathepsin S, a major cystein protease that process Ii chain (J Immunol 2005, 175: 5324).  These results suggested that mycobacteria specifically block the surface export of peptide-loaded, class II molecules and by doing so attenuate the adaptive anti-TB immune response dependent on CD4+ T cell activation.  Based upon these findings, We recently engineered a novel recombinant BCG expressing active human cathepsin S (rBCG-hcs) and demonstrated that such Immunology-dictated reshaping of the conventional vaccine reverses the defect in class II expression and antigen presentation observed with wild-type BCG (J Immunol, 2007, In press).

DEA, Univ Claude Bernard, Microbiology
Doctorat de 3eme Cycle, Univ Claude Bernard, Microbiology
PhD, Univ Claude Bernard, Immunology.
Recent Publications:
  • •Horacio B, Jim S, Hmama Z, Av-Gay Y.  Mycobacterium avium ssp paratuberculosis PtpA is an endogenous tyrosine phosphatase secreted during infection.  Infect Immun, 2006, 74:6540-46.
  • •Deghmane AE, Soualhine H, Sendide K, Itoh S, Tam A, Noubir S, Talal A, Lo R, Toyoshima S, Av-Gay Y, Hmama Z.  Mycobacterial dihydrolipoamide dehydrogenase mediates retention of the coat protein coronin-1 on M. bovis BCG vacuoles leading to phagosome maturation arrest. J. Cell Sci. 120:2796-806, 2007.
  • •Soualhine H, Deghmane AE, Sun J, Mak K, Amina Talal A, Av-Gay Y, Hmama Z. Mycobacterium bovis BCG secreting active cathepsin S stimulates expression of mature MHC class II molecules and antigen presentation in human macrophages. J Immunol, 179:5137-45, 2007.
  • •Sun J, Deghmane AE, Soualhine H, Hong T, Bucci C, Solodkin A, Hmama Z.  Mycobacterium Bovis BCG inhibits Rab7-RILP interaction in the macrophage. J Leuk Biol., 82:1437-45, 2007.
  • •Horacio B, Kadamba G. Papavinasasundaram KG, Wong D, Hmama Z, Av-Gay Y.  Mycobacterium tuberculosis virulence is mediated by PtpA dephosphorylation of human VPS33B. Cell Host & Microbe 3: 316-22, 2008.
  • •Sun J, Lau AT, Wang X, Liao TA, Zoubeidi A, Hmama Z. A Broad-Range of Recombination Cloning Vectors in Mycobacteria, Plasmid 62: 158-165, 2009.
  • •Chao J, Wong D, Zheng X, Poirier V, Bach H, Hmama Z, Av-Gay Y. Protein kinases and phosphatases signaling in Mycobacterium tuberculosis physiology and pathogenesis. Biochim Biophys Acta 1804:620-627, 2010.
  • •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  5(1):e8769, 2010.