Airway epithelial cells as a novel intracellular host reservoir forCryptococcusspores

Abstract

AbstractHuman fungal pathogens cause an estimated 1.5 million annual deaths andCryptococcus neoformans, an inhaled facultative intracellular pathogen, is at the top of the WHO’s priority list of fungal pathogens.Cryptococcuscauses disease when it disseminates out of the lung and into the brain which can occur years after initial exposure. However, the mechanisms of bothCryptococcusdissemination and latency are still unclear. One potential reason that these mechanisms remain unknown is that the morphotype used for the vast majority of studies is the yeast form and not the dormant and stress resistant spore morphotype. The inhalation ofCryptococcusspores initiates infections and recent evidencein vivohas shown that spores display unique host-pathogen interactions and are able to escape the lung and disseminate to the brain more readily than yeast. Due to the difficulties associated working with these spores, little is known about how they interact with host cells.AirwayEpithelialCells (AECs), which cover the entire alveolar surface and comprise 24% of all cells in the human lung parenchyma, likely have instant and extensive contact with inhaled spores. In this study, we demonstrated thatCryptococcusspores can invade AECs bothin vitroandin vivo. Once inside spores can germinate and subsequently replicate, persist and/or escape. This ability to enter AECs correlates with a preferential ability of spore to cross AEC barriers. Together our work indicates AECs may serve as a previously ignored intracellular host reservoir and challenges the current paradigms of bothCryptococcusdissemination and latency.