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

Date Published: June 27, 2019

Publisher: Public Library of Science

Author(s): Naomi M. Walsh, Michael R. Botts, Andrew J. McDermott, Sébastien C. Ortiz, Marcel Wüthrich, Bruce Klein, Christina M. Hull, Amariliz Rivera.


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.

Partial Text

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. Inert particles such as dust and pollen are cleared effectively, as are most microbes. However, many disease-causing organisms such as bacteria and fungi that gain entry via the lung have developed strategies for evading clearance, allowing them to colonize the lung and ultimately escape and disseminate to other tissues [1].

Spores and yeast of Cryptococcus are likely natural infectious particles in human cryptococcosis and both have been shown to cause disease in a mouse model of infection [9,10]. However, the mechanisms by which Cryptococcus and other inhaled fungal pathogens escape the lung are poorly understood. Here, we evaluated the behaviors of spores and yeast from diverse strain backgrounds in a murine intranasal infection model to determine mechanisms of dissemination and disease. By comparing yeast- and spore-mediated infections, we discovered that disease outcomes can differ tremendously between infectious particles of the same organism, even when derived from the same strains. Most strikingly, using Cryptococcus yeast strains that typically do not cause disease in mice, we showed that spores derived from crosses between those avirulent yeast strains are fully virulent in mice and cause 100% fatal disease with symptoms reflecting meningoencephalitis. Thus, the nature of the infectious particle (yeast vs. spore) establishes the nature of the disease and its outcome (up to 75 days later). This finding is particularly intriguing because all visible spores in the mouse lung germinate into yeast within the first 18 hours after infection. As such, different relationships that spores and yeast establish with the host in the first day after infection confer differences in disease outcomes 2.5 months post-infection. These findings suggest that early interactions with the host innate immune response in the lung set the stage for the nature of disease.




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