Paul M. Allen, Ph.D. (Director)

DEPARTMENT OF Pathology & Immunology
Eric J. Brown, M.D.; Timothy L. Ratliff, Ph.D.; Philip D. Stahl, Ph.D.
Keywords: AIDS, infection, mycobacteria, cell biology, immunology

Mycobacterium avium-intracellulare (MAC) is the most frequent opportunistic pathogen causing bacteremia in patients with AIDS. Evidence of MAC infection can be found in 50 percent of autopsied AIDS patients, and MAC accelerates death in infected patients. Currently used anti-MAC antibiotics are toxic and generally ineffective. Tuberculosis is once again on the rise, and multiple antibiotic resistant organisms have arisen in several areas of outbreak. Attempts at more effective therapy are hampered by lack of knowledge about the basic biology of mycobacteria. To fill this need we have developed a multicomponent program with five distinct projects.

The first project examines the receptors used for recognition and phagocytosis of mycobacteria. This project also examines the roles that specific receptors have in the subsequent intracellular localization of the organisms and in development of disease in a SCID mouse model of mycobacteria infection.

In the second project, we are examining the strategies that mycobacteria use to avoid intracellular killing. Particular emphasis is on the biochemical, electron microscopic and immunologic characterization of the mycobacteria-containing phagosome.

The third project is a dissection of the intracellular events that occur after engulfment of mycobacteria by macrophages. Exploiting novel assays in broken and semi-permeable cells, this project examines the molecular requirements for fusion of mycobacteria-containing phagosomes with endosomes and lysosomes.

A detailed examination of the interaction of mycobacteria-infected cells with T cells is the focus of the fourth project. The aim of this project is to define protective epitopes in normal hosts. Further analysis of mycobacteria infection in immunodeficient SCID mice defines precisely the role of antigen-specific CD8 and CD4 T cells in host protection and in macrophage killing of mycobacteria in vivo and in vitro.

Finally, we are testing the hypothesis that mycobacteria infection specifically modulates macrophage effector functions in response to cytokine stimulation. These studies will determine the molecular nature of the defect in macrophages infected in the absence of T cells, as in AIDS. Together, the highly interactive projects that constitute this program bring the tools of modern molecular and cell biology and immunology to the study of mycobacteria infection. We expect several novel avenues for development of therapeutics and vaccines to arise from these studies.