Cryptococcus neoformans (C. neoformans) is a pathogenic fungus with a global distribution. Humans become infected by inhaling the fungus from the environment, and the fungus initially colonizes the lungs. If the immune system fails to contain C. neoformans in the lungs, the fungus can disseminate to the blood and invade the central nervous system, resulting in fatal meningoencephalitis particularly in immunocompromised individuals including HIV/AIDS patients. Following brain invasion, C. neoformans will encounter host defenses involving resident as well as recruited immune cells in the brain. To overcome host defenses, C. neoformans possesses multiple virulence factors capable of modulating immune responses. The outcome of the interactions between the host and C. neoformans will determine the disease progression. In this review, we describe the current understanding of how C. neoformans migrates to the brain across the blood–brain barrier, and how the host immune system responds to the invading organism in the brain. We will also discuss the virulence factors that C. neoformans uses to modulate host immune responses.

Cryptococcus neoformans is an encapsulated pathogenic fungus that initially infects the lung but can migrate to the central nervous system (CNS), resulting in meningoencephalitis. The organism causes the CNS infection primarily in immunocompromised individuals including HIV/AIDS patients, but also, rarely, in immunocompetent individuals. In HIV/AIDS patients, limited inflammation in the CNS, due to impaired cellular immunity, cannot efficiently clear a C. neoformans infection. Antiretroviral therapy (ART) can rapidly restore cellular immunity in HIV/AIDS patients. Paradoxically, ART induces an exaggerated inflammatory response, termed immune reconstitution inflammatory syndrome (IRIS), in some HIV/AIDS patients co-infected with C. neoformans. A similar excessive inflammation, referred to as post-infectious inflammatory response syndrome (PIIRS), is also frequently seen in previously healthy individuals suffering from cryptococcal meningoencephalitis. Cryptococcal IRIS and PIIRS are life-threatening complications that kill up to one-third of affected people. In this review, we summarize the inflammatory responses in the CNS during HIV-associated cryptococcal meningoencephalitis. We overview the current understanding of cryptococcal IRIS developed in HIV/AIDS patients and cryptococcal PIIRS occurring in HIV-uninfected individuals. We also describe currently available animal models that closely mimic aspects of cryptococcal IRIS observed in HIV/AIDS patients.

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