McGwire, Bradford

Bradford S. McGwire, MD, PhD is an Assistant Professor of Infectious Diseases and Internal Medicine and a member of the Center for Microbial Interface Biology. Dr. McGwire joined the faculty in 2004.

Dr. McGwire’s research focuses on the mechanisms by which the related pathogenic protozoa Leishmania and trypanosomes (T. cruzi and T. brucei) establish and maintain infection in their mammalian hosts. In Leishmania, the surface metalloprotease (gp63) is an important virulence factor for both receptor mediated binding to and intraphagolysosomal survival of parasites in macrophages. This protease as well as other surface proteins appears also to be important for recognition of and invasion of extracellular matrix (ECM) proteins during early stages of infection. The current aims of this work are to: 1) characterize the interactions of Leishmania with ECM proteins; 2) identify the surface protein(s) mediating these interactions, and; 3) characterize the proteolytic degradation of ECM proteins and the contribution of this to the outcome of infection.

Homologues of gp63 are expressed in Trypanosoma cruzi and Trypanosoma brucei. We have found that gp63 is expressed in all life stages of T. cruzi but appears to be a different isoform in infective insect stages. In addition our work has shown that gp63 is important for infection of host cells in vitro. The current aims of this work are: 1) structural characterization of the different gp63 isoforms in T. cruzi; 2) identification of the domains in gp63 that are important for infectivity, and; 3) characterization of the mechanisms by which gp63 influences T. cruzi infection.  

The McGwire lab also has an interest in the role of innate antimicrobial factors such as antimicrobial peptides (AMPs) in the infection process. Gp63 appears to be involved in the resistance of Leishmania to certain AMPs due to their proteolytic degradation. Other AMPs (cathelicidins) are highly active against both Leishmania and the trypanosomes and have been used to diminish ongoing infection of mice with T. brucei. The aims of this work are to: 1) characterize the interactions of AMPs with parasite surface membranes; 2) characterize the degradation of certain AMPs by gp63, and; 3) the design of AMPs with enhanced antiparasitic activity.  

Selected Publications

Kulkarni, M. M, McMaster, W. R., Kamysz, E. Kamysz, W. Engman, D. M. and McGwire, B.S.  2006. The surface-metalloprotease of the parasitic protozoan, Leishmania, protects against antimicrobial peptide-induced apoptotic killing. Mol. Microbiology. 62 (5): 1484-1497.

Young J.D. and McGwire B.S. 2005. Infliximab and reactivation of cerebral toxoplasmosis.
N. Engl. J. Med. 353(14):1530-1.

McGwire, B. S., Olson, C. L., Tack, B. F. and Engman, D. M. 2003. Killing of African trypanosomes by antimicrobial peptides. J Infect Dis. 188(1):146-52.

McGwire, B. S., Chang, K.-P. and Engman, D. M. 2003. Migration through the extracellular matrix by the parasitic protozoan Leishmania is enhanced by surface metalloprotease gp63. Infect Immun. 71(2):1008-10.

McGwire, B. S., O'Connell, W. A., Chang, K.-P., Engman, D. M. 2002. Extracellular release of the glycosylphosphatidylinositol (GPI)-linked Leishmania surface metalloprotease, gp63, is independent of GPI phospholipolysis: implications for parasite virulence. J Biol Chem. 277(11):8802-9.

Brittingham, A., Chen, G., McGwire, B. S., Chang, K.-P. and Mosser, D. M. 1999. Interaction of leishmania gp63 with cellular receptors for fibronectin. Infect. Immun. 67(9):4477-84.

 McGwire Laboratory Personnel

Present

Past