Academic Journal
Bet-hedging antimicrobial strategies in macrophage phagosome acidification drive the dynamics of Cryptococcus neoformans intracellular escape mechanisms.
| Τίτλος: | Bet-hedging antimicrobial strategies in macrophage phagosome acidification drive the dynamics of Cryptococcus neoformans intracellular escape mechanisms. |
|---|---|
| Συγγραφείς: | Dragotakes, Quigly, Jacobs, Ella, Ramirez, Lia Sanchez, Yoon, Olivia Insun, Perez-Stable, Caitlin, Eden, Hope, Pagnotta, Jenlu, Vij, Raghav, Bergman, Aviv, D'Alessio, Franco, Casadevall, Arturo |
| Πηγή: | PLoS Pathogens; 7/11/2022, Vol. 18 Issue 7, p1-25, 25p |
| Θεματικοί όροι: | Cryptococcus neoformans, Acidification, Video microscopy, Phagocytosis, Phagosomes, Fungal growth, Lysosomes, Macrophages |
| Περίληψη: | The fungus Cryptococcus neoformans is a major human pathogen with a remarkable intracellular survival strategy that includes exiting macrophages through non-lytic exocytosis (Vomocytosis) and transferring between macrophages (Dragotcytosis) by a mechanism that involves sequential events of non-lytic exocytosis and phagocytosis. Vomocytosis and Dragotcytosis are fungal driven processes, but their triggers are not understood. We hypothesized that the dynamics of Dragotcytosis could inherit the stochasticity of phagolysosome acidification and that Dragotcytosis was triggered by fungal cell stress. Consistent with this view, fungal cells involved in Dragotcytosis reside in phagolysosomes characterized by low pH and/or high oxidative stress. Using fluorescent microscopy, qPCR, live cell video microscopy, and fungal growth assays we found that the that mitigating pH or oxidative stress reduced Dragotcytosis frequency, whereas ROS susceptible mutants of C. neoformans underwent Dragotcytosis more frequently. Dragotcytosis initiation was linked to phagolysosomal pH, oxidative stresses, and macrophage polarization state. Dragotcytosis manifested stochastic dynamics thus paralleling the dynamics of phagosomal acidification, which correlated with the inhospitality of phagolysosomes in differently polarized macrophages. Hence, randomness in phagosomal acidification randomly created a population of inhospitable phagosomes where fungal cell stress triggered stochastic C. neoformans non-lytic exocytosis dynamics to escape a non-permissive intracellular macrophage environment. Author summary: Host macrophages do not have prior information about the pathogens they ingest. Hence, they have no information about the threats from or vulnerabilities of microbes they phagocytose. Consequently, macrophages must hedge bets in their defense strategies when combatting pathogens with unknown vulnerabilities. This results in a wide variety of phagosomal environments which maximizes the overall antimicrobial ability of the entire population of phagosomes but individual phagosomes may or may not be hostile to a specific pathogen. Using live cell microscopy to track in vitro infections, viability staining, qPCR, and enzyme activity assays we investigated the relationship between phagosomal cell stress and Dragotcytosis, or fungal macrophage-to-macrophage transfer. We have found that Cryptococcus neoformans game this system by transferring to new phagosomes when it finds itself in too hostile of an environment. Specifically, this process is triggered when the yeast experiences overwhelming cellular stress. These findings illustrate a system in which C. neoformans is detecting cellular damage as a trigger for the transfer process and the stochastic nature of microbe-macrophage interactions at the cellular level. [ABSTRACT FROM AUTHOR] |
| Copyright of PLoS Pathogens is the property of Public Library of Science and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) | |
| Βάση Δεδομένων: | Complementary Index |
καταχωρήστε σχόλιο πρώτοι!