Abstract
A common feature shared by systemic fungal pathogens of environmental origin, such as Cryptococcus neoformans, is their ability to adapt to mammalian core body temperature. In C. neoformans, this adaptation is accompanied by Ccr4-mediated decay of ribosomal protein mRNAs. Here we use the related, but thermo-intolerant species Cryptococcus amylolentus to demonstrate that this response contributes to host-temperature adaptation and pathogenicity of cryptococci. In a C. neoformans ccr4Δ mutant, stabilized ribosomal protein mRNAs are retained in the translating pool, and stress-induced transcriptomic changes are reduced in comparison with the wild type strain, likely due to ineffective translation of transcription factors. In addition, the mutant displays increased exposure of cell wall glucans, and recognition by Dectin-1 results in increased phagocytosis by lung macrophages, linking mRNA decay to adaptation and immune evasion.
Highlights
A common feature shared by systemic fungal pathogens of environmental origin, such as Cryptococcus neoformans, is their ability to adapt to mammalian core body temperature
ribosomal proteins (RPs) mRNA decay correlates with host-temperature adaptation
To determine if temperature-induced rapid degradation of RP transcripts was specific to C. neoformans, we assessed RP transcript decay in the thermointolerant relative C. amylolentus
Summary
A common feature shared by systemic fungal pathogens of environmental origin, such as Cryptococcus neoformans, is their ability to adapt to mammalian core body temperature. In C. neoformans, this adaptation is accompanied by Ccr4-mediated decay of ribosomal protein mRNAs. Here we use the related, but thermo-intolerant species Cryptococcus amylolentus to demonstrate that this response contributes to host-temperature adaptation and pathogenicity of cryptococci. The mutant displays increased exposure of cell wall glucans, and recognition by Dectin-1 results in increased phagocytosis by lung macrophages, linking mRNA decay to adaptation and immune evasion. The ability of C. neoformans to thrive within a macrophage phagosome has been attributed to interactions with predatory amoeba in the soil11 It follows, that increasing global surface temperatures may select for thermotolerance, and concomitantly may lead to the emergence of new fungal pathogens. We report that immediate RP transcript decay and repression is absent in C. amylolentus following host-temperature stress, suggesting that this response may be necessary for hosttemperature adaptation and pathogenicity. The work presented here suggests that regulated mRNA decay is a pathogen-specific response to host-temperature stress in cryptococci that promotes adaptation via regulation of transcriptome and translatome reprogramming, and demonstrates a link between temperature adaptation and innate immune evasion in the Cryptococci
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