Abstract
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.
Highlights
Through the act of breathing, the mammalian lung is regularly exposed to a wide variety of airborne particles, such as dust, air pollutants, and microbes
Little is known about how inhaled spores from human fungal pathogens cause infections and spread to other parts of the body
We discovered that parental yeast that are not virulent produced spores that were fully virulent and caused fatal meningitis
Summary
Through the act of breathing, the mammalian lung is regularly exposed to a wide variety of airborne particles, such as dust, air pollutants, and microbes. Both physical and immunological barriers have evolved to keep the lung clear of foreign agents and facilitate efficient respiration. One successful inhaled human pathogen is Cryptococcus This environmental fungus is found in association with soil, tree bark, and bird droppings, and upon inhalation can escape the lung and cause fatal fungal meningoencephalitis [2]. Immunocompromised patients are most at risk of developing cryptococcosis, but disease among healthy individuals is on the rise worldwide [3]. Hundreds of thousands of people a year develop cryptococcosis and die, due in large part to limited treatment options for invasive fungal diseases and challenges in treating brain infections [6]
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