Immunity induced by cryptococcal morphological strains in CD4+ T cell-deficient hosts

About This Grant

PROJECT SUMMARY Cryptococcal meningoencephalitis (CME) is responsible for more than 15% of the total deaths of AIDS patients. The disease claims hundreds of thousands of lives each year, with global mortality rates of ~70% de- spite antifungal therapies. Unfortunately, there is no vaccine clinically available or in clinical trials for cryptococ- cosis. We previously showed that the morphotype of this fungus has a profound effect on its interaction with various hosts. In mammalian models of cryptococcosis, the yeast form is pathogenic while the filamentous form is not. We established that the transcription factor Znf2, which drives filamentous growth, is a powerful anti-virulence regulator. Cryptococcal cells overexpressing ZNF2 (ZNF2oe) are avirulent and elicit strong and long-lasting protective immunity, which serves as an effective vaccine against subsequent lethal challenges. Importantly, we showed that once mice are vaccinated with ZNF2oe cells, their CD4+ T cells are dispen- sable for protection at the time of fungal challenge. Furthermore, vaccination with ZNF2oe cells pro- vides significant protection against cryptococcosis even in hosts with pre-existing CD4+ T cell defi- ciency (mimics AIDS patients). These findings are important because the majority of cryptococcosis patients are AIDS patients with low CD4+ T cell counts, and our preclinical studies suggest that cryptococcal vaccines could be effective in these individuals. The specific goals of this exploratory R21 application are to identify cell types (Aim 1) and cytokine profiles (Aim 2) important for ZNF2oe vaccine-induced immunity and host protection in CD4+ T cell-defi- cient hosts. The findings from the proposed work will identify correlates of protection (COPs) that will help guide the design of safer and effective subunit protein vaccines or nucleic acid-based vaccines in the future. Our long-term goal is to develop vaccines that could protect the most vulnerable populations from deadly cryp- tococcal meningoencephalitis.