GROWTH WITHIN MACROPHAGES INCREASES THE EFFICIENCY OF MYCOBACTERIUM-AVIUM IN INVADING OTHER MACROPHAGES BY A COMPLEMENT RECEPTOR-INDEPENDENT PATHWAY

Infections caused by organisms of the Mycobacterium avium complex occu r in approximately 50 to 60% of patients with AIDS. M. avium is an int racellular pathogen that survives and multiplies within mononuclear ph agocytes, In this study, we investigated the uptake of M. avium grown within macrophages (intracellular growth M. avium [IG]) by a second ma crophage compared with M. avium cultured in broth (extracellular growt h M. avium [EG]). The results shelved that IG was six- to eightfold mo re efficient than EG in entering macrophages, In addition, while an an ti-CR3 antibody was able to inhibit approximately 60% of EG uptake by macrophages, it failed to inhibit the entry of IG, In contrast to EG, IG uptake into macrophages was significantly inhibited in the presence of anti-beta 1-integrin and anti-transferrin receptor antibodies, Ent ry into macrophages by alternate receptors was associated with resista nce to tumor necrosis factor alpha (TNF-alpha) stimulation. While stim ulation with TNF-alpha resulted in inhibition of the growth of EG, it was not associated with inhibition of intracellular growth of IG. Inve stigation of the reason why M. avium is able to sense the changes in t he intracellular environment triggering a change to the invasive pheno type suggests a direct relationship with macrophage apoptosis. These r esults suggest that intracellular growth is associated with novel mech anisms of M. avium uptake of macrophages and that those mechanisms app ear to offer advantages to the bacteria in escaping the host defense.