ACTIVATION OF HUMAN MACROPHAGE FUNGISTATIC ACTIVITY AGAINST HISTOPLASMA-CAPSULATUM UPON ADHERENCE TO TYPE-1 COLLAGEN MATRICES

Human monocyte/macrophages (M phi) were adhered to extracellular matri x proteins, and the intracellular growth of Histoplasma capsulatum (Hc ) yeasts were quantified and compared with their growth in M phi adher ed to plastic. Freshly isolated monocytes and cultured monocyte/derive d M phi adhered to type 1 collagen gels, but not to nongelled collagen -, fibronectin-, laminin-, or vitronectin-coated surfaces, demonstrate d significant fungistatic activity against He yeasts. Activation of M phi developed immediately upon adherence to the collagen matrices (1 h ) and did not require additional time in culture. In addition, many of the yeasts were digested by 24 h postinfection. M phi adhered to coll agen maintained their fungistatic activity for up to 4 days, during wh ich time monolayers cultured on plastic were destroyed. Culture of M p hi in the presence of IFN-gamma or TNF-alpha for 24 h before infection did not augment the fungistatic activity of collagen-adherent M phi. Likewise, culture of monocytes on collagen gels with IL-3, granulocyte -M phi CSF (CM-CSF) or M phi CSF (M-CSF) for 7 days did not enhance M phi fungistatic activity above that obtained by monocytes cultured on collagen alone. The mechanism(s) of M phi-mediated fungistasis was not associated with production of toxic oxygen radicals, nitric oxide, or the restriction of intracellular iron. However, experiments with hors eradish peroxidase-labeled gold colloids and immunoelectron microscopy demonstrated that phagolysosomal fusion, which is minimal in He-infec ted M phi adhered to plastic, is enhanced significantly at both 1 h an d 24 h postinfection in M phi adhered to collagen matrices. These data suggest that in vivo, matrix-bound M phi may express a previously unr ecognized antifungal activity that proceeds in the absence of exogenou s cytokines and is mediated, in part, by overcoming the capacity of He yeasts to inhibit M phi phagolysosomal fusion.