Methamphetamine Enhances Cryptococcus neoformans Melanization, Antifungal Resistance, and Pathogenesis in a Murine Model of Drug Administration and Systemic Infection.

Methamphetamine (METH) is a major public health and safety problem in the United States. Chronic METH abuse is associated with a 2-fold-higher risk of HIV infection and, possibly, additional infections, particularly those that enter through the respiratory tract or skin. Cryptococcus neoformans is an encapsulated opportunistic yeast-like fungus that is a relatively frequent cause of meningoencephalitis in immunocompromised patients, especially in individuals with AIDS. C. neoformans melanizes during mammalian infection in a process that presumably uses host-supplied compounds such as catecholamines. l-3,4-Dihydroxyphenylalanine (l-Dopa) is a natural catecholamine that is frequently used to induce melanization in C. neoformans. l-Dopa-melanized cryptococci manifest resistance to radiation, phagocytosis, detergents, and heavy metals. Using a systemic mouse model of infection and in vitro assays to critically assess the impact of METH on C. neoformans melanization and pathogenesis, we demonstrated that METH-treated mice infected with melanized yeast cells showed increased fungal burdens in the blood and brain, exacerbating mortality. Interestingly, analyses of cultures of METH-exposed cryptococci supplemented with l-Dopa revealed that METH accelerates fungal melanization, an event of adaptation to external stimuli that can be advantageous to the fungus during pathogenesis. Our findings provide novel evidence of the impact of METH abuse on host homeostasis and increased permissiveness to opportunistic microorganisms.

Coccidioidomycosis: Epidemiology, Fungal Pathogenesis, and Therapeutic Development.

PURPOSE OF REVIEW: Coccidioidomycosis can result from the inhalation of infectious spores of Coccidioides species (spp.) immitis or posadasii. Clinical manifestations range from mild flu-like disease to severe disseminated infection that can require life-long therapy. Burden of this mycosis is high in the southwest region of the USA where it is well characterized, and in many areas of Mexico and Latin America where it is inadequately characterized. Here, we provide historical data and current knowledge on Coccidioides spp. pathogenesis as well as recent progress in therapeutic and vaccine development against coccidioidomycosis. RECENT FINDINGS: The virulence mechanisms of Coccidioides spp. are largely unknown; however, production and regulation of a spherule glycoprotein, ammonium production, and melanization have all been proposed as integral factors in Coccidioides spp.' pathogenesis. Therapeutic options are limited and not 100% effective, but individualized treatment with triazoles or amphotericin B over the course of pulmonary or disseminated infection can be effective in resolution of coccidioidomycosis. Human immunization has not been achieved but efforts are ongoing. SUMMARY: Advances in therapeutic and vaccine development are imperative for the prevention and treatment of coccidioidomycosis, especially for those individuals at risk either living or traveling to or from endemic areas.