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.

Keywords: CD4+ T cells; CNS; CSF; Cryptococcus neoformans; HIV/AIDS; IFN-γ; IRIS; NK cells; PIIRS; T cells; TNF-α; antiretroviral therapy (ART); biomarkers; brain; central nervous system; chemokines; cryptococcal meningitis; cryptococcosis; cytokines; fungal pathogenesis; fungus; inflammation; macrophages; meningoencephalitis; microglia; monocytes.

Figure 1

Graphic representation of murine models of cryptococcal IRIS. (A) RAG-1^−/− mice on C57BL/6 background were intranasally (i.n.) infected with 500 C. neoformans strain 1841 (Serotype D). 2 × 10⁶ CD4⁺ T cells isolated from naive mice were adoptively transferred to the infected RAG-1^−/− mice on day 32 post-infection (dpi) via tail vein injection. Analyses were performed on day 40 dpi [34]. (B) RAG-1^−/− mice on C57BL6 background were intranasally infected with 100 C. neoformans strain H99 (Serotype A). 1 × 10⁶ CD4⁺ T cells isolated from naïve mice were adoptively transferred to the infected mice on week 3 post-infection (wpi) via tail vein injection. Analyses were performed on 4 wpi [35]. (C) Wild-type C57BL/6 mice were intravenously (i.v.) infected with 1 × 10⁶ C. neoformans strain 52D (Serotype D). Samples were collected on day 7, 14, 21, 28 and 35 post-infection (dpi) [36].