Mechanisms of balancing the immune response during cryptococcal meningoencephalitis

Univ Of Maryland, College Park, College Park MD

Investigators

Abstract

Project Summary Cryptococcosis is an opportunistic fungal infection that is caused by Cryptococcus neoformans and often occurs in immunocompromised individuals including HIV/AIDS patients. Although the infection starts in the lung via inhalation of the pathogenic fungus, the most common manifestation of cryptococcosis is meningoencephalitis, which is a leading cause of mortality of HIV/AIDS patients and accounts for proximately 181,000 deaths worldwide annually. The high susceptibility of HIV/AIDS patients to C. neoformans infection is attributed to their impaired cellular immunity. Consequently, C. neoformans proliferates in the brain without control, leading to microbe-mediated brain damage. Antiretroviral therapy (ART) is a major advance in treating HIV/AIDS patients by restoring cellular immune responses. However, after initiation of ART, up to 30% of HIV/AIDS patients with cryptococcosis develop immune reconstitution inflammatory syndrome (IRIS), an aberrant excessive immune response leading to host-mediated brain damage. Furthermore, post-infectious inflammatory response syndrome (PIIRS) occurs frequently in HIV-negative patients with cryptococcal meningoencephalitis. Therefore, a robust immune response is required for controlling the fungal growth; however, the immune response must be tightly controlled to avoid host-mediated brain damage during cryptococcal meningoencephalitis. A critical gap in our understanding remains: what are the mechanisms of maintaining the balance between protective immune responses and immunopathology during cryptococcal meningoencephalitis-associated IRIS? IL-10 is an important cytokine with anti-inflammatory properties and its production was enhanced in the cerebrospinal fluid of HIV/AIDS patients during cryptococcal IRIS. Based on clinical data and our preliminary murine studies, we hypothesize that IL-10 is critically involved in balancing the immune responses during cryptococcal meningoencephalitis-associated IRIS. We will test the hypothesis in a murine model that closely mimics cryptococcal IRIS of HIV/AIDS patients, by addressing the following aims: (1) To determine the mechanism(s) involved in regulation of the immune responses by IL-10 during cryptococcal meningoencephalitis-associated IRIS; (2) To determine the mechanism(s) involved in induction of IL-10 in the brain during cryptococcal meningoencephalitis-associated IRIS. If successful, the findings from this study would be fundamental for understanding regulation of immune balance during cryptococcal meningoencephalitis-associated IRIS and provide scientific basis for targeting this cytokine aiming at controlling deleterious inflammation in the brain of cryptococcal IRIS/AIDS patients.