Cryptococcal Immune Reconstitution Inflammatory Syndrome: From Clinical Studies to Animal Experiments

Abstract

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.

Global trends in Cryptococcus and its interactions with the host immune system: a bibliometric analysis

“…Following the administration of ART, although there is a rapid restoration of cellular immunity in individuals with HIV/AIDS-associated Cryptococcus infection, there is a propensity for the emergence of immune reconstitution inflammatory syndrome (IRIS). This phenomenon is characterized by a pronounced inflammatory response within the central nervous system, correlated with a heightened mortality rate among affected individuals ( 49 , 50 ). Cryptococcal IRIS induces an aberrant inflammatory cascade that eventuates in host-mediated neuropathology ( 51 ).…”

Alternatively activated lung alveolar and interstitial macrophages promote fungal growth

“…C. neoformans causes meningitis mainly in immunocompromised individuals including patients with HIV/AIDS, but also, rarely, in immunocompetent individuals. 1 , 69 Following infection, the immune system of healthy individuals can eliminate or contain the fungal cells in the lung, which is likely attributed to Th1/M1 responses. 31 , 70 In contrast, in patients with HIV/AIDS, C. neoformans grows in the lung, leading to brain dissemination and infection.…”

Isolated cryptococcal osteomyelitis in the setting of immune reconstitution inflammatory syndrome

“…The infection may sometimes lie dormant and manifest as part of immune reconstitution inflammatory syndrome (IRIS) in immunocompromised patients initiated on antiretroviral therapy. 4 Nonetheless, cryptococcal IRIS has also been reported in immunocompetent individuals. 5 As the immune system strengthens in a patient with a preexisting opportunistic infection, inflammation and inflammatory cytokines ramp up and can cause devastating side effects.…”