Immunology and Cell Biology of Mycobacterium – Host Cell Interactions
Jeff S. Schorey
George Craig, Jr. Professor
Ph.D., University of Texas Health Science Center at San Antonio
Postdoctoral, Washington University School of Medicine
Mycobacteria have a long history as pathogenic organisms and are the etiological agents of such well known diseases as tuberculosis and leprosy. Tuberculosis is a particularly deadly disease accounting for approximately 1.5 million deaths annually and is the second leading cause of death due to an infectious organism. A further concern in recent years has been the dramatic increase in the number of individuals infected with multi-drug resistant strains of Mycobacterium tuberculosis. Other pathogenic mycobacteria include M. avium; an increasingly common pathogen associated with COPD and CF patients as well as a major opportunistic pathogen in AIDS patients within the United States.
My lab focuses on the interaction between mycobacteria and its’ host cell the macrophage. As intracellular pathogens, mycobacteria require invasion of macrophages for their survival. However, macrophages, which function as part of the innate immune system, also serve an essential role in controlling a mycobacterial infection. Interestingly, macrophages infected with pathogenic, relative to non-pathogenic mycobacteria, show limited production of inflammatory mediators (i.e. cytokines, chemokines, nitric oxide, etc.) which are required to control bacterial growth. However, the molecular mechanisms responsible for these differences in macrophage response are not well defined. Our studies have identified a number of macrophage-signaling pathways activated upon mycobacterial invasion including the mitogen activated protein kinases and have shown that production of inflammatory mediators are dependent on the activation of these pathways. Moreover, we have determined that macrophages infected with pathogenic M. avium and M. tuberculosis strains show only limited activation of these signaling systems. Studies are ongoing to further characterize the macrophage signaling molecules activated upon mycobacterial infection, how these responses differ upon infection with pathogenic and non-pathogenic mycobacteria and to characterize the mycobacterial components which initiate or inhibit these macrophage signals. We are particularly interested in studying the importance of glycopeptidolipids (GPL) (a major surface component of M. avium) in modulating macrophage-signaling responses and in mycobacterial pathogenesis.
Additional studies in the laboratory have focused on the transport of mycobacterial components from the phagosome where the mycobacteria reside to other compartments within the macrophage. Interestingly, we have found that some mycobacterial components can be released from infected cells via exosomes. Exosomes are small 50 to 100 nm membrane vesicles released from hematopoietic and non-hematopoietic cells which likely play an important role in intercellular communication. We have found that exosomes released from M. tuberculosis-infected macrophages can modulate the innate and acquired immune response both in vitro and in vivo and we are addressing the importance of exosome biogenesis in M. tuberculosis pathogenesis. We have also been pursuing some of the practical applications of our exosome studies. Through a project funded by the Bill and Melinda Gates Foundation we have found that exosomes carrying mycobacterial proteins can be isolated from TB patient serum and our data suggest that exosomes may provide a unique biomarker for active disease. Recent studies also indicate that exosomes released from infected macrophages carry a number of dominant TB antigens and that these exosomes can provide protection against M. tuberculosis in a mouse aerosol infection model suggesting a potential use as a TB vaccine.
Most experiments in the laboratory involve cellular and molecular approaches in combination with immunological methods. The goal of our research is to help control mycobacterial infections through a better understanding of the Mycobacterium-host interactions.
Figure: Beads coated with glycopeptidolipids (GPLs) show delayed trafficking to a lysosomal compartment. nsGPL: apolar GPLs, Lp core: lipopeptide core of GPL, Pc: phosphatidylcholine, ManLAM: mannose-capped lipoarabinomannan (positive control).
1. Bhatnagar, S. and Schorey, J.S. (2006) Elevated MAP kinase signaling and increased macrophage activation in cells infected with a glycopeptidolipid-deficient Mycobacterium avium. Cellular Microbiology. 8; 85-96.
2. Yadav, M., Clark, L. and Schorey, J.S. (2006) Macrophage’s pro-inflammatory response to a mycobacterial infection is dependent on Sphingosine kinase mediated activation of PI-PLC, PKC, ERK1/2 and PI-3 kinase. Journal of Immunology 176; 5494-5503.
3. Sweet, L. and Schorey, J.S. (2006) Glycopeptidolipids from Mycobacterium avium promote macrophage activation in a TLR2- and MyD88-dependent manner. Journal of Leukocyte Biology. 80; 415-423.
4. Yadav, M. and Schorey, J.S. (2006) The -glucan receptor Dectin-1 functions together with TLR2 to mediate macrophage activation by mycobacteria. Blood. 108; 3168-3175.
5. Bhatnagar S., Shinagawa K., Castellino F.J., Schorey J.S. (2007) Exosomes released from macrophages infected with intracellular pathogens stimulate a proinflammatory response in vitro and in vivo. Blood. 110; 3234-44.
6. Bhatnagar, S. and Schorey J.S. (2007) Exosomes released from infected macrophages contain Mycobacterium avium glycopeptidolipids and are proinflammatory. Journal of Biological Chemistry. 282; 25779-89.
7. Giri, P.K and Schorey, J.S. (2008) Exosomes derived from M. Bovis BCG infected macrophages activate antigen-specificCD4+ and CD8+ T cells in vitro and in vivo. PLoS ONE. 3(6):e2461.
8. Sweet, L., Zhang, W., Torres-Fewell, H., Serianni, A., Boggess, W. and Schorey, J.S. (2008) Mycobacterium avium glycopeptidolipids require specific acetylation and methylation patterns for signaling through TLR2. Journal of Biological. Chemistry. 283; 33221-33231. (JIF: 5.440)
9. Muralidharan-Chari, V., Hoover, H., Clancy, J., Schweitzer, J., Suckow, M.A., Schroeder, V., Castellino, F.J., Schorey, J.S., D'Souza-Schorey, C. (2009) ADP-ribosylation factor 6 regulates tumorigenic and invasive properties in vivo. Cancer Research. 69; 2201-2209.
10. Sweet, L., Singh, P.P., Azad, A.K., Schlesinger, L.S. and Schorey, J.S. (2010) Mannose receptor-dependent delay in phagosome maturation by Mycobacterium avium glycopeptidolipids. Infection & Immunity. 78; 518-526.
11. Giri, P.K., Kruh, N.A., Dobos, K.M. and Schorey, J.S. (2010) Proteomic analysis identifies highly antigenic proteins on exosomes from M. tuberculosis-infected and culture filtrate protein-treated macrophages. Proteomics. 10; 3190-3202.
12. Singh, P.P, LeMaire, C., Tan, J., Zeng E. and Schorey, J.S. (2011) Exosomes released from M. tuberculosis-infected cells can suppress IFN-γ mediated activation of naïve macrophages. PLoS ONE 6(4):e18564.
13. Singh, P.P., Smith, V.L., Karakousis, P.C. and Schorey, J.S. (2012) Exosomes isolated from Mycobacterium tuberculosis-infected mice or cultured macrophages can recruit and activated immune cells in vitro and in vivo. J. Immunol. 189; 777-785.