Mechanisms of vaccine protection against AIDS-associated Cryptococcus infection

ABSTRACT Fungal infections are often an under recognized pathogenic cause of host mortality. The rise in use of immunosuppressant therapeutics over the past decades has resulted in the steady increase of susceptible populations throughout the world. Moreover, mortality rates from invasive fungal infection remain unacceptably high due to the frequent inability of antifungal drugs to efficiently control fungal growth. Currently no fungal vaccines exist even as host mortality rates due to pathogenic fungi including Aspergillus fumigatus (Af), Cryptococcus neoformans (Cn), and Cryptococcus gatti (Cg), continue to increase. Therefore, there is a clear medical need for antifungal vaccines that can help protect susceptible populations. In previous studies we determined that heat-killed preparations of Cn-fbp1 (HK-Fbp1) mutant yeast cells can function as an effective and novel vaccine candidate. Furthermore, we recently uncovered that vaccination with HK-Fbp1 can confer cross-protection against different fungal species including A. fumigatus, C. albicans, and C. gatti. These findings suggest that upon HK-Fbp1 vaccination there is activation of conserved antifungal mechanisms that can protect against diverse fungal species. In the studies proposed in this supplement we seek to expand on the goals of the parental grant to focus on deciphering the mechanisms of vaccine-induced cross-protection against Af. We hypothesize that vaccination with HK-Fbp1 confers defense against Af via activation of trained innate immune cells. The concept of innate immune training has become a growing and exciting field of research. Various studies support the notion that the host?s history of infection can affect responses to exposure to subsequent infections. In previous studies the Rivera lab demonstrated that defense against Af is dependent on myeloid cells and can occur even in the absence of the entire lymphoid compartment. Thus, we hypothesize that this novel HK-Fbp1 vaccine confers protection against Af infection via trained immunity of myeloid cells. We will investigate this hypothesis via the following independent aims: 1) Decipher the roles of innate cells in HK-Fbp1, vaccine- induced protection against fungal challenges, and 2) Define the role of IFN signaling in the instruction of antifungal, pulmonary trained innate cells. These proposed studies will complement and expand the scope of the parental grant to provide novel insight on how HK-Fbp1 vaccine shapes broadly protective antifungal defense. These studies will further advance the search for a pan-fungal vaccine.