Infectious particle identity determines dissemination and disease outcome for the inhaled human fungal pathogen Cryptococcus

The majority of invasive human fungal pathogens gain access to their human hosts via the inhalation of spores from the environment into the lung, but relatively little is known about this infectious process. Among human fungal pathogens the most frequent cause of inhaled fatal fungal disease is Cryptococcus, which can disseminate from the lungs to other tissues, including the brain, where it causes meningoencephalitis. To determine the mechanisms by which distinct infectious particles of Cryptococcus cause disseminated disease, we evaluated two developmental cell types (spores and yeast) in mouse models of infection. We discovered that while both yeast and spores from several strains cause fatal disease, there was a consistently higher fungal burden in the brains of spore-infected mice. To determine the basis for this difference, we compared the pathogenesis of avirulent yeast strains with their spore progeny derived from sexual crosses. Strikingly, we discovered that spores produced by avirulent yeast caused uniformly fatal disease in the murine inhalation model of infection. We determined that this difference in outcome is associated with the preferential dissemination of spores to the lymph system. Specifically, mice infected with spores harbored Cryptococcus in their lung draining lymph nodes as early as one day after infection, whereas mice infected with yeast did not. Furthermore, phagocyte depletion experiments revealed this dissemination to the lymph nodes to be dependent on CD11c+ phagocytes, indicating a critical role for host immune cells in preferential spore trafficking. Taken together, these data support a model in which spores capitalize on phagocytosis by immune cells to escape the lung and gain access to other tissues, such as the central nervous system, to cause fatal disease. These previously unrealized insights into early interactions between pathogenic fungal spores and lung phagocytes provide new opportunities for understanding cryptococcosis and other spore-mediated fungal diseases. Author summary Little is known about how inhaled spores from human fungal pathogens cause infections and spread to other parts of the body. The most frequent cause of inhaled fatal fungal disease is Cryptococcus, which causes meningitis. To understand how Cryptococcus causes disease, we evaluated pathogenesis of two types of cells (spores and yeast) in a mouse model of infection. We compared yeast strains that cannot cause disease to the spore offspring they produced during sexual reproduction. We discovered that parental yeast that are not virulent produced spores that were fully virulent and caused fatal meningitis. This difference was associated with movement of spores to the lymph system; mice infected with spores had Cryptococcus in their lung draining lymph nodes, but mice infected with yeast did not. Furthermore, when we infected mice that lacked immune cells in their lungs, no spores were found in their lymph nodes. This indicates that instead of protecting mice from the spore infection, the immune cells moved spores out of the lung to the lymph system where spores could then spread to the brain. These insights into interactions between pathogenic fungal spores and lung immune cells provide new opportunities for understanding cryptococcosis and other spore-mediated fungal diseases.