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Human Macrophages Do Not Require Phagosome Acidification to Mediate Fungistatic/Fungicidal Activity against Histoplasma capsulatum¹

Simon L. Newman^2,*, Lisa Gootee^*, Jeremy Hilty and Randall E. Morris

^* Department of Medicine, Division of Infectious Diseases, and Department of Cell Biology, Neurobiology, and Anatomy, University of Cincinnati College of Medicine, Cincinnati, OH 45267

Histoplasma capsulatum (Hc) is a facultative intracellular fungus that modulates the intraphagosomal environment to survive within macrophages (M). In the present study, we sought to quantify the intraphagosomal pH under conditions in which Hc yeasts replicated or were killed. Human M that had ingested both viable and heat-killed or fixed yeasts maintained an intraphagosomal pH of 6.4–6.5 over a period of several hours. These results were obtained using a fluorescent ratio technique and by electron microscopy using the 3-(2,4-dinitroanilo)-3'-amino-N-methyldipropylamine reagent. M that had ingested Saccharomyces cerevisae, a nonpathogenic yeast that is rapidly killed and degraded by M, also maintained an intraphagosomal pH of 6.5 over a period of several hours. Stimulation of human M fungicidal activity by coculture with chloroquine or by adherence to type 1 collagen matrices was not reversed by bafilomycin, an inhibitor of the vacuolar ATPase. Human M cultured in the presence of bafilomycin also completely degraded heat-killed Hc yeasts, whereas mouse peritoneal M digestion of yeasts was completely reversed in the presence of bafilomycin. However, bafilomycin did not inhibit mouse M fungistatic activity induced by IFN-. Thus, human M do not require phagosomal acidification to kill and degrade Hc yeasts, whereas mouse M do require acidification for fungicidal but not fungistatic activity.

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