Methamphetamine Impairs IgG1-Mediated Phagocytosis and Killing of Cryptococcus neoformans by J774.16 Macrophage- and NR-9640 Microglia-Like Cells

Abstract

The prevalence of methamphetamine (METH) use is estimated at ~35 million people worldwide, with over 10 million users in the United States. Chronic METH abuse and dependence predispose the users to participate in risky behaviors that may result in the acquisition of HIV and AIDS-related infections. Cryptococcus neoformans is an encapsulated fungus that causes cryptococcosis, an opportunistic infection that has recently been associated with drug users. METH enhances C. neoformans pulmonary infection, facilitating its dissemination and penetration into the central nervous system in mice. C. neoformans is a facultative intracellular microorganism and an excellent model to study host-pathogen interactions. METH compromises phagocyte effector functions, which might have deleterious consequences on infection control. In this study, we investigated the role of METH in phagocytosis and antigen processing by J774.16 macrophage- and NR-9460 microglia-like cells in the presence of a specific IgG1 to C. neoformans capsular polysaccharide. METH inhibits antibody-mediated phagocytosis of cryptococci by macrophages and microglia, likely due to reduced expression of membrane-bound Fcγ receptors. METH interferes with phagocytic cells' phagosomal maturation, resulting in impaired fungal control. Phagocytic cell reduction in nitric oxide production during interactions with cryptococci was associated with decreased levels of tumor necrosis factor alpha (TNF-α) and lowered expression of Fcγ receptors. Importantly, pharmacological levels of METH in human blood and organs are cytotoxic to ~20% of the phagocytes. Our findings suggest that METH abrogates immune cellular and molecular functions and may be deadly to phagocytic cells, which may result in increased susceptibility of users to acquire infectious diseases.