Three models of vaccination strategies against cryptococcosis in immunocompromised hosts using heat-killedCryptococcus neoformansΔsgl1

Abstract

AbstractVaccines are one of the greatest medical accomplishments to date, yet no fungal vaccines are currently available in humans mainly because opportunistic mycoses generally occur during immunodeficiencies necessary for vaccine protection. In previous studies, a live, attenuatedCryptococcus neoformansΔsgl1mutant accumulating sterylglucosides was found to be avirulent and protected mice from a subsequent lethal infection even in absence of CD4+T cells, a condition most associated with cryptococcosis (e.g., HIV). Here, we tested three strategies of vaccination against cryptococcosis. First, in our preventative model, protection was achieved even after a 3-fold increase of the vaccination window. Second, because liveC. neoformansΔsgl1-vaccinated mice challenged more than once with WT strain had a significant decrease in lung fungal burden, we testedC. neoformansΔsgl1as an immunotherapeutic. We found that therapeutic administrations of HKC. neoformansΔsgl1subsequent to WT challenge significantly improve the lung fungal burden. Similarly, therapeutic administration of HKC. neoformansΔsgl1post WT challenge resulted in 100% or 70% survival depending on the time of vaccine administration, suggesting that HK Δsgl1is a robust immunotherapeutic option. Third, we investigated a novel model of vaccination in preventing reactivation from lung granuloma usingC. neoformansΔgcs1. Remarkably, we show that administration of HK Δsgl1prevents mice from reactivating Δgcs1upon inducing immunosuppression with corticosteroids or by depleting CD4+T cells. Our results suggest that HK Δsgl1represents a clinically relevant, efficacious vaccine that confers robust host protection in three models of vaccination against cryptococcosis even during CD4-deficiency.ImportanceCryptococcosis results in ∼180,000 global deaths per year in immunocompromised individuals. Current antifungal treatment options are potentially toxic, lacking in areas of need, and exhibit limited efficacy. In addition to these lackluster therapeutic options, no fungal vaccines are currently available for clinical use. Due to the increasing rate of immunocompromised individuals, there is a dire need for the development of improved antifungal therapeutics. Presently, we have demonstrated the high efficacy of a clinically relevant heat-killed mutant strain ofCryptococcus neoformansin inducing advantageous host protection in three models of vaccination against cryptococcosis during immunodeficiencies most associated with this disease.