Mycobacterial infection have emerged as important opportunistic infections in patients with the Acquired Immunodeficiency Syndrome (AIDS). Infections with Mycobacterium tuberculosis and Mycobacterium avium-intracellular (MAI) are particularly important. Our ability to formulate rational strategies for the prevent and treatment of mycobacterial diseases in patients with AIDS is dependent on our knowledge of the basic biology of the host-pathogen interaction. The over-all objective of this proposal is to learn more about the role of the complement system and of monocyte complement receptors in phagocytosis of mycobacteria and to build on our recent findings that phagocytosis of M. tuberculosis is mediated by complement receptors on monocytes and by C3 on the bacterial surface.
Specific aims are to: a) Identify the acceptor molecules for C3 on the M. tuberculosis surface; b) Determine if C3 fixation to M. tuberculosis is antibody-independent; c) Determine the influence of Fab fragments of anti-C3 antibody on adherence of M. tuberculosis to monocytes and of Fab fragments of anti-acceptor molecule on adherence and complement fixation; d) Determine if monocyte CR3 and CR1 receptors comigrate with M. tuberculosis during phagocytosis; e) Determine if phagocytosis of M. Tuberculosis is correlated with CR1 and/or CR3 receptor number; f) Select mutant M. tuberculosis that do not fix C3 and determine if they are phagocytized by monocytes; g) Purify the M. tuberculosis C3-acceptor molecule(s).
