ABSTRACT
Candida auris is an emerging nosocomial fungal pathogen associated with life-threatening invasive disease due to its persistent colonization, high level of transmissibility and multi-drug resistance. Aggregative and non-aggregative growth phenotypes for C. auris strains with different biofilm forming abilities, drug susceptibilities and virulence characteristics have been described. Using comprehensive transcriptional analysis we identified key cell surface adhesins that were highly upregulated in the aggregative phenotype during in vitro and in vivo grown biofilms using a mouse model of catheter infection. Phenotypic and functional evaluations of generated null mutants demonstrated crucial roles for the adhesins Als5 and Scf1 in mediating cell-cell adherence, coaggregation and biofilm formation. While individual mutants were largely non-aggregative, in combination cells were able to co-adhere and aggregate, as directly demonstrated by measuring cell adhesion forces using single-cell atomic force spectroscopy. This co-adherence indicates their role as complementary adhesins, which despite their limited similarity, may function redundantly to promote cell-cell interaction and biofilm formation. Functional diversity of cell wall proteins may be a form of regulation that provides the aggregative phenotype of C. auris with flexibility and rapid adaptation to the environment, potentially impacting persistence and virulence.
ABSTRACT
Candida auris is an emerging nosocomial fungal pathogen associated with life-threatening invasive disease due to its persistent colonization, high level of transmissibility and multi-drug resistance. Aggregative and non-aggregative growth phenotypes for C. auris strains with different biofilm forming abilities, drug susceptibilities and virulence characteristics have been described. Using comprehensive transcriptional analysis we identified key cell surface adhesins that were highly upregulated in the aggregative phenotype during in vitro and in vivo grown biofilms using a mouse model of catheter infection. Phenotypic and functional evaluations of generated null mutants demonstrated crucial roles for the adhesins Als5 and Scf1 in mediating cell-cell adherence, coaggregation and biofilm formation. While individual mutants were largely non-aggregative, in combination cells were able to co-adhere and aggregate, as directly demonstrated by measuring cell adhesion forces using single-cell atomic force spectroscopy. This co-adherence indicates their role as complementary adhesins, which despite their limited similarity, may function redundantly to promote cell-cell interaction and biofilm formation. Functional diversity of cell wall proteins may be a form of regulation that provides the aggregative phenotype of C. auris with flexibility and rapid adaptation to the environment, potentially impacting persistence and virulence.
ABSTRACT
The nuclear envelope (NE) is a double-membrane system surrounding the nucleus of eukaryotic cells. A large number of proteins are localized in the NE, performing a wide variety of functions, from the bidirectional exchange of molecules between the cytoplasm and the nucleus to chromatin tethering, genome organization, regulation of signaling cascades, and many others. Despite its importance, several aspects of the NE, including its protein-protein interactions, remain understudied. In this work, we present NucEnvDB, a publicly available database of NE proteins and their interactions. Each database entry contains useful annotation including a description of its position in the NE, its interactions with other proteins, and cross-references to major biological repositories. In addition, the database provides users with a number of visualization and analysis tools, including the ability to construct and visualize protein-protein interaction networks and perform functional enrichment analysis for clusters of NE proteins and their interaction partners. The capabilities of NucEnvDB and its analysis tools are showcased by two informative case studies, exploring protein-protein interactions in Hutchinson-Gilford progeria and during SARS-CoV-2 infection at the level of the nuclear envelope.
