Eosinophil-induced airway remodelling as novel gateway and therapeutic target for Cryptococcus neoformans dissemination

Cryptococcosis is a severe fungal disease caused by Cryptococcus neoformans (CN), with a high mortality rate of 40-60%. Following inhalation, CN primarily infects the respiratory system and spreads to the central nervous system, causing life-threatening meningoencephalitis. Current treatments, such as amphotericin B and fluconazole, are in 8% of the cases not exclusively protective against breakthrough meningitis and are associated with long term decrease (>1 year) in quality of live post-treatment in the form of cranial nerve impairments, depression in 67% to 44% of the cases, and neurocognitive decline in 59% to 41% of the cases. This urges the need for a deeper understanding of CNs pathogenesis to improve therapeutic options. In previous studies, we developed a mouse model of cryptococcosis to investigate host-pathogen interactions, by using advanced imaging techniques and engineered CN strains to track real-time progression of CN infection. Our findings identified eosinophils as unexpected and novel key players in the respiratory immune response to CN. Flow cytometry revealed a rapid accumulation of CD11cint eosinophils in the peribronchial lung regions. The airway damaging properties of eosinophils leads to our hypothesis that eosinophils may provide a gateway for CN
dissemination to the brain. Moreover, it was shown previously that overexpression of the eosinophil stimulating interleukin 5 (IL-5) resulted in decreased survival rate in a murine aerosol model of cryptococcosis. To elucidate the potential adverse role of eosinophils in cryptococcosis, we will manipulate the IL-5 axis and use single-cell RNA sequencing and spatial transcriptomics to examine eosinophil-epithelium interactions. Our goal is not only to understand how eosinophils contribute to epithelial damage and systemic CN spread, but also to identify novel biomarkers for cryptococcosis progression, out ruling the current cryptococcal antigen test that requires dissemination and the presence cryptococcal material in the bloodstream, potentially leading to prophylactic treatments for patients at risk of cryptococcal meningoencephalitis. This research could inform the clinical use and repurposing of existing IL-5 antagonists, such as benralizumab, FDA/EMA approved and currently in use for treatment of eosinophil induced
asthma, to reduce eosinophil-induced damage in cryptococcosis, offering a path toward targeted and potentially preventive therapies.