Mechanisms of vaccine protection against AIDS-associated Cryptococcus infection

Rutgers Biomedical And Health Sciences, Newark NJ

Investigators

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Abstract

ABSTRACT Invasive fungal infections are emerging diseases that kill over 1.5 million people each year. Among them Cryptococcus neoformans is the leading cause of fungal meningitis that is account for 15% of AIDS-related deaths. The treatment option for fungal infections is very limited and there is no fungal vaccine available in clinical use. Therefore, there is an unmet need to develop new treatments against this life-threatening fungal infection. Our recent studies uncovered that Fbp1, a F-box protein in the ubiquitin-mediated proteolytic pathway, acts as a master regulator of C. neoformans immunogenicity and identified fbp1 mutant as a new vaccine candidate. We found that vaccination with heat-killed fbp1 (HK-fbp1) conferred significant protection from a subsequent challenge with not only virulent parental strain H99 in mice, but also showed cross protection against C. gattii and other fungal infections, including Aspergillus fumigatus. Treating C. neoformans infected animals with HK- fbp1 vaccine also showed protection. Thus, HK-fbp1 is an optimal vaccine candidate with broad protection, and a better understanding of how HK-fbp1 induces protection will facilitate the future development of new treatments against cryptococcosis and other fungal infections. During the last funding period, we demonstrated that the HK-fbp1 vaccine protection is dependent on the activation of innate and adaptive immune responses that included the rapid recruitment and maturation of CCR2+ monocytes and the enhanced activation of CD8 and CD4 Th1/Th17 responses. Such protection is dependent on IFN- We also identified an Fbp1 E3 ligase substrate Crk1 that is critical for cell size regulation and Fbp1 mediated immunogenicity, leading to a better mechanistic insight. In ongoing studies, we determined that the addition of CpG oligodeoxynucleotides (CpG- ODN) to HK-fbp1 leads to improved vaccine efficacy. Importantly, HK-fbp1+CpG-ODN induced protection against Cryptococcus infection after intramuscular (i.m.) administration whereas i.m. HK-fbp1 alone is unable to protect. The immune mechanisms of this substantially improved protection mediated by the adjuvanted vaccine remain unknown. Based on our published and unpublished observations we hypothesize that the success of HK-fbp1 as an effective vaccine is critically linked to the enhanced capacity of fbp1 to induce protective innate and adaptive immune responses. Our overarching goal is to systematically decipher the immune mechanisms of vaccine-induced protection and to define the function of specific Fbp1-regulated targets that shape the immunogenicity of C. neoformans to develop a vaccine applicable for human use in the future. To test our hypothesis and achieve our goal, we propose to 1) decipher the distinct contributions of innate and adaptive immunity from adjuvanted HK-fbp1 vaccine-induced protection, and 2) define immunogenic factors in HK-fbp1 to develop an improved vaccine against fungal infections. These studies will advance our understanding of host- pathogen interactions involved in the immune regulation by Cryptococcus and guide the design of effective vaccines critical for the control of fungal infections.