Bacterial metabolites induce cell wall remodeling, antifungal resistance, and immune recognition of commensal fungi
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Abstract
The fungus Candida albicans commensally colonizes mucosal surfaces in healthy individuals but can cause both superficial mucosal and life-threatening disseminated infections. The balance between commensalism and pathogenicity is complex and depends on factors including host and fungal genetic background, the host environment, and fungal interactions with local microbes. The major interaction interface of C. albicans with the host is its multilayered cell wall, which is dynamic and highly responsive to the surrounding environment. Therefore, factors that influence the fungal cell wall will directly impact C. albicans -host interactions. Our work demonstrates that multiple physiologically-relevant gastrointestinal bacteria influence fungal cell wall composition during co-culture with C. albicans, including as complex communities derived from the gut. Using Escherichia coli as a model, we show that bacterial-induced fungal cell wall remodeling occurs rapidly and is mediated by secreted bacterial metabolite(s). Fungal mutant analysis revealed that the high osmolarity glycerol (HOG) pathway, which is critical for responding to environmental stresses, has an important role in regulating this cell wall remodeling phenotype through the Sln1 histidine kinase. Importantly, bacterial-mediated fungal cell wall remodeling increases C. albicans resistance to the echinocandins, increases recognition by both dectin-1 and dectin-2, and decreases recognition by human IgA. Overall, this work comprehensively characterizes an interaction between C. albicans and common gastrointestinal bacteria that has important implications for fungal biology and host interactions.
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(Fig 4B). However, rlm1Δ/Δ and sko1Δ/Δ had a reduced capacity to remodel during co-culture, indicating that they are positive regulators of bacterial-mediated cell wall remodeling (Fig 4B). The reduced capacity of sko1Δ/Δ to remodel was also apparent based on its mannan histograms, which had more overlap between conditions than that of the SN152 wildtype (Fig 4C). After identifying transcription factors required for the full remodeling phenotype, we wanted to determine which signaling pathways were responsible for transcription factor activation. Many of the relevant pathways are controlled by mitogen-activated protein kinase (MAPK) cascades; therefore, we chose representative MAPKs from three signaling pathways with well-established roles in the regulation of cell wall remodeling. We found that mkc1Δ/Δ, from the PKC pathway, and …
(Fig 4B). However, rlm1Δ/Δ and sko1Δ/Δ had a reduced capacity to remodel during co-culture, indicating that they are positive regulators of bacterial-mediated cell wall remodeling (Fig 4B). The reduced capacity of sko1Δ/Δ to remodel was also apparent based on its mannan histograms, which had more overlap between conditions than that of the SN152 wildtype (Fig 4C). After identifying transcription factors required for the full remodeling phenotype, we wanted to determine which signaling pathways were responsible for transcription factor activation. Many of the relevant pathways are controlled by mitogen-activated protein kinase (MAPK) cascades; therefore, we chose representative MAPKs from three signaling pathways with well-established roles in the regulation of cell wall remodeling. We found that mkc1Δ/Δ, from the PKC pathway, and cek1Δ/Δ, from the Cek1-mediated pathway, had a normal remodeling response (Fig 4D). Representative kinases from the high osmolarity glycerol (HOG) pathway, hog1Δ/Δ and pbs2Δ/Δ, had a reduced capacity to remodel in response to E. coli co-culture, similar to sko1Δ/Δ and rlm1Δ/Δ (Fig 4D).
Do you show for comparison the change in cell wall mannan content over this time period for these different mutants in monoculture, other than for the mutant in C?
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e standard growth conditions for C. albicans, YPD media at 30°C, also allows for growth of E. coli
Similarly, if you are interested in realistically modeling interactions, it seems non-ideal to choose a medium optimized for yeast growth. It seems like choosing a medium that more closely represents the conditions found in the host would be a lot more compelling.
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), in monoculture or co-culture with Escherichia coli strain MC1061
I am curious about your choice of strain here. From what I can tell MC1061 is an engineered cloning strain. If you are interested in modeling commensal interactions, it seems like it would be preferable to use a commensal strain or isolate that better reflects a native E. coli?
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