Mechanisms of cryptococcal IRIS

About This Grant

Project Summary Due to the progressive depletion of CD4+ T cells, HIV/AIDS patients are more susceptible to infection of Cryptococcus neoformans, an encapsulated fungus that is listed by WHO as a pathogen of critical priority. An estimated 112,000 people die from C. neoformans infections globally each year. C. neoformans is a leading cause of mortality among HIV/AIDS patients. Antiretroviral therapy (ART) can rapidly restore CD4+ T cells in HIV/AIDS patients, representing a major advance in the treatment of HIV-infections. However, the rapid recovery of CD4+ T cells in HIV/AIDS patients that co-infected with C. neoformans after initiation of ART often causes an exaggerated inflammatory response in the central nervous system (CNS), termed immune reconstitution inflammatory syndrome (IRIS). Cryptococcal IRIS is considered as a life-threating condition, as it can lead to a high mortality rate during ART among HIV/AIDS-associated IRIS patients who have a cryptococcal infection. Clinical studies have shown that cryptococcal IRIS is associated with a substantial CNS recruitment of immune cells and enhanced secretions of inflammatory cytokines. However, the cellular and molecular mechanisms involved in cryptococcal IRIS are poorly understood. In particular, it remains to be determined which leukocyte subset(s) and cytokine(s) mediate the death during cryptococcal IRIS and how CD4+ T cell responses are regulated during cryptococcal IRIS. These questions are hard to be answered without animal studies. Using a novel murine model of C. neoformans infection to closely mimic HIV/AIDS-associated cryptococcal IRIS, we will define the mechanisms of cryptococcal IRIS by addressing the following aims: 1) To identify the leukocyte subset(s) accounting for lethal cryptococcal IRIS; 2) To identify the cytokine(s) accounting for lethal cryptococcal IRIS; 3) To identify the factors regulating CD4+ T cells responses during cryptococcal IRIS. Successful completion of this study would gain novel insights into the cellular and molecular mechanisms that mediate lethal immune responses during cryptococcal IRIS and identify potential targets for treatment of HIV/AIDS-associated cryptococcal IRIS patients.