The long term objective for the continuation of this project is to gain an understanding of the mechanism of inhibition of normal human host defense against the opportunistic fungi, Candida albicans, by a key psychoactive metabolite of marijuana, delta-9 tetrahydrocannabinol (THC). This organism from the normal flora is usually nonpathogenic except when the host is immunocompromised as in AIDS patients. We have developed important information to indicate that the strong link between human natural killer (NK) cells and polymorphonuclear neutrophils (PMN) for defense against C albicans growth in vitro can be broken by THC. We have identified that NK cells can react rapidly to C. albicans by release of cytokines that can both recruit and activate neutrophils to inhibit Candida growth. The finding that THC can inhibit both neutrophil antifungal activity and NK release of neutrophil activating factors needs to be further pursued in greater detail. The attempt will be made to identify specifically if internal or external killing of C albicans by neutrophils is separately affected by THC. The 4 microbicidal mechanisms, phagocytosis, superoxide anion production, degranulation of primary granules, exocytosis of lactoferrin from secondary granules, will be analyzed with respect to THC suppression. Analysis of the ability of tumor necrosis factor (TNF), Interferon gamma (IFNg), granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin 8 (IL8) to reconstitute neutrophil function inhibited by THC will provide an insight into the mechanism of action of each of these cytokines. The ability of THC to inhibit not only fungicidal function but also cytokine release from neutrophils and NK cells will also be investigated to determine if the inhibition is at the transcriptional, translational or secretory level. Additionally, characterization of the THC receptors on NK cells and neutrophils will lead to a biochemical understanding of the interaction of THC with these 2 effector cells.
