1975. 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 capsular polysaccharide. METH inhibits antibody-mediated phagocytosis of EPZ031686 cryptococci by macrophages and microglia, likely due to reduced expression of membrane-bound Fc 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-) and lowered expression of Fc 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. is an encapsulated fungus that causes cryptococcosis, an opportunistic infection primarily in HIV-infected patients (7). Globally, this eukaryotic microorganism is responsible for approximately 223,000 cases of life-threatening meningoencephalitis and 181,000 deaths per year (8). Interestingly, recent cases in the United States of systemic cryptococcosis in intravenous drug users and a daily cannabis smoker suggest that drug abuse may exacerbate the disease even in the absence of HIV infection (9, 10). In this regard, METH enhances infection of the respiratory system and dissemination to the CNS of rodents by promoting fungal attachment, alteration of the polysaccharide capsule composition, release of immunosuppressive capsular material, and biofilm formation (11, 12). Thus, is an excellent model organism to answer questions regarding host-pathogen interactions in the setting of METH due to the accessibility to specific antibodies (Abs), cell lines, and animal models (13). At pharmacological concentrations, METH exerts immunosuppressive effects on dendritic cells (14), neutrophils (15), and macrophages (16). Particularly, macrophages are important in EPZ031686 controlling and containing infection in the lungs (17). Fc receptors (FcRs) on macrophages can bind and mediate phagocytosis of Ab-opsonized yeast cells (18). Abs to the glucuronoxylomannan (GXM), the main component of the capsular polysaccharide, can modulate the infection (19). For instance, interaction of IgG1 complexes with related FcRs facilitates either fungal killing, fungal growth inhibition through macrophage-mediated Ab-dependent cytotoxicity, macrophage phagocytosis, or neutrophil activation (20). In fact, passive capsule binding IgG1 therapy has been efficacious in inducing protective Rabbit Polyclonal to ATP5S immunity, enhancing antifungal effectiveness, and prolonging survival in murine models of infection (19, 21). is a facultative intracellular pathogen that resides in acidic phagosomes within macrophages (22). Cryptococci easily replicate and release abundant amounts of polysaccharide-enclosed vesicles inside phagocytic cells that accumulate in their EPZ031686 phagosome, resulting in the escape of candida cells through lytic and nonlytic exocytosis (23,C25). Even though METH compromises the ability of macrophages to keep up acidic phagolysosomes (13, 16), the effect of this drug of abuse within the intracellular effects of specific Abs within the fate of a microbe within murine macrophages has not been extensively investigated. The EPZ031686 intimate connection of with macrophages is an ideal system to examine the part of METH in Ab function (13). Similarly and particularly important to cryptococcal illness, positron emission tomography offers demonstrated that the highest build up and slowest clearance EPZ031686 of METH in humans happen in the lungs and mind, respectively, with these organs becoming main disease-related focuses on of the fungus (26). In the brain, microglia, the resident monitoring cells of the CNS, act as its primary active immune defense and are associated with (27), suggesting that they play an important role controlling the infection (27, 28). In addition, microglia have been associated with METH-induced neurotoxicity (29, 30). Although microglia are vital in controlling microbial brain cells colonization (27), their relationships with remain understudied. With this study, we explored the effect of METH on Ab-mediated phagocytosis and antigenic control by J774.16 macrophage-.