Immunology and Cell Biology of Mycobacterium - Host Cell Interactions

Jeff S. Schorey     Associate Professor, Department of Biological Sciences  Ph.D., University of Texas Health Science Center at San Antonio Postdoctoral, Washington University School of Medicine

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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 over 2 million deaths annually and is the 2nd 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, one of the most common opportunistic pathogen in AIDS patients within the United States and M. Leprae, the causative agent of leprosy.

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 this difference in macrophage response is 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 (a major surface component of M. avium) in modulating macrophage-signaling responses and in mycobacterial pathogenesis. 

Additional studies are ongoing to address the macrophage receptors engaged during infection with pathogenic and non-pathogenic mycobacteria and how engagement of these specific receptors promotes the macrophage proinflammatory response.  We have recently described a novel role for the macrophage beta-glucan receptor Dectin-1 in cooperation with the Toll-like receptor 2 in promoting cytokine and chemokine production by macrophages upon mycobacterial infection.  The Dectin-1 has been extensively characterized as an important receptor in the host response to fungal infections but our studies indicate Dectin-1’s role in promoting a successful immune response to pathogens is likely much broader then original recognized and suggests that a study of Dectin-1 in the context of other non-fungal pathogens including mycobacteria is needed.  These studies are ongoing.   

  

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-macrophage interaction.

 

Signaling Pathways Activated in Macrophages Upon Mycobacterial Infection

 

Selected Publications:

Schorey, J.S., Carroll, M.C. and Brown, E.J. (1997) A macrophage invasion mechanism of pathogenic mycobacteria. Science. 277; 1091-1092

Bohlson, S.S., Strasser, J.A., Bower, J.J., and Schorey, J.S. (2001) The role of complement in Mycobacterium avium pathogenesis: In vivo and in vitro analysis of the host response to infection in the absence of complement component C3. Infection and Immunity. 69; 7729-7735.

Roach, S.K. and Schorey, J.S. (2002) Differential regulation of p38 mitogen activated protein kinase phosphorylation in macrophages infected with Mycobacterium.  Infection and Immunity. 70; 3040-3052.

Krzywinska, E. and Schorey, J.S. (2003) Characterization of genetic Differences Between the Mycobacterium Avium subsp. Avium Strains of Diverse Virulence With a Focus on the Glycopeptidolipid Biosynthesis Cluster.  Veterinary Microbiology. 91; 249-64.

Schorey, J.S. and Cooper, A.M. (2003) Macrophage signaling upon mycobacterial infection: The MAP kinases lead the way.  Cellular Microbiology.  5; 133-139. (Cover Photo).

Kelley, V.A. and Schorey, J.S. (2003) Endosome Fusion and Iron Acquisition is Required for Mycobacterial Retention in an Early Phagosomal Compartment in Primary Macrophages.  Molecular Biology of the Cell.  14; 3366-77.

Sato, J., Schorey, J.S., Ploplis, V.A., Haalboom, E., Krahule, L. and Castellino, F.J. (2003) Involvement of Fibrinolytic Proteins in Dissemination and Extracellular Matrix Deposition Following a Mycobacterium avium Infection.  Am. J. of Pathology. 163; 517-31.

Yadav, M., Roach, S.K. and Schorey, J.S. (2004) Increased MAPK activity and TNF-alpha production associated with Mycobacterium smegmatis but not M. avium infected macrophages requires prolonged stimulation of the CaM/caMK and cAMP/PKA pathways.  J. Immunol.  172; 5588-5597.

Krzywinska, E., Krzywinski, J., and Schorey, J.S. (2004) Phylogeny of Mycobacterium avium strains inferred from glycopeptidolipid biosynthesis pathway genes.  Microbiology. 150; 1699-1706.

Krzywinska, E., Krzywinski, J., and Schorey, J.S. (2004) Naturally occurring horizontal gene transfer and homologous recombination in Mycobacterium.  Microbiology. 150; 1707-1712.

Kelley, V.A. and Schorey, J.S.  (2004) Modulation of cellular Phosphatidylinositol 3-phosphate levels in primary macrophages affects heat-killed but not viable M. avium’s transport through the phagosome maturation process.  Cellular Micro. 6; 973-985.

Roach, S.K., Lee, S.B. and Schorey, J.S.  (2005) Mycobacterial induced TNF-α Production in Macrophages Requires a PKA and p38 MAPK Dependent Activation of the Transcription Factor CREB. Infect. Immun. 73; 514-522.

Krzywinska, E., Bhatnagar, S. Sweet, L., Chatterjee, D. and Schorey, J.S. (2005) Modification of Mycobacterium avium glycopeptidolipid structure results in bacilli of attenuated virulence. Molecular Micro. 56; 1262-1273.

Lee, S.B. and Schorey, J.S.  (2005) Activation and MAPK Regulation of Transcription Factors Ets and NF-kB in Mycobacterial Infected Macrophages and Their Role in TNF-a and NOS2 Promoter Function. Infect. Immun. 73; 6499-6507.

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 Micro.  8; 85-96.

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.  J. Immunol.  176; 5494-5503.

Sweet, L. and Schorey, J.S. (2006) Glycopeptidolipids from Mycobacterium avium promote macrophage activation in a TLR2- and MyD88-dependent manner. J. Leukocyte Biol. 80: 415-423.

Yadav, M. and Schorey, J.S.  (2006) The b-glucan receptor Dectin-1 functions together with TLR2 to mediate macrophage activation by mycobacteria. Blood. 108:3168-3175.

Schorey, J.S. (2006) Macrophage activation: `Tis the way the WNT blows. Blood. 108: 785.

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.

Bhatnagar S and Schorey J.S. (2007) Exosomes released from infected macrophages contain Mycobacterium avium glycopeptidolipids and are proinflammatory. J Biol Chem. 282: 25779-89.

Schorey, J.S. and Lawrence C. (2008) The pattern recognition receptor Dectin-1: from fungi to mycobacteria.  Current Drug Targets. 9: 123-129.

Schorey, J.S. and Bhatnagar, S. (2008) Exosome function: From tumor immunology to pathogen biology.  Traffic. 9: 871-81.

Giri, G.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.