Identification ofCandida albicansregulatory genes governing mucosal infection

Abstract

The fungus Candida albicans thrives on a variety of human mucosae, yet the fungal determinants that contribute to fitness on these surfaces remain underexplored. Here, by screening a collection of C. albicans deletion strains in a mouse model of oral infection (oropharyngeal candidiasis), we identify several novel regulatory genes that modulate the fitness of the fungus in this locale. We investigate in detail the interplay between the host mucosa and one of the identified mutants and establish that the C. albicans transcription regulator CUP9 is a key determinant of mucosal colonisation. Deletion of cup9 resulted in the formation of more foci of colonisation and heightened persistence in infected tongues. Furthermore, the cup9 mutant produced longer and denser filaments in the oral mucosa without eliciting an enhanced local immune response. Consistent with its role in oral colonisation, we show that CUP9's top target of regulation is a major effector of Candida's adherence to buccal cells. Finally, we establish that CUP9 also governs the interplay of the fungus with vaginal epithelial cells and has a role in vaginal infections, another common mucosal disease associated with Candida. Thus, our findings reveal a mechanism whereby C. albicans can regulate proliferation on mucosal surfaces.

Oral Candidiasis: A Disease of Opportunity

“…Secretion of proinflammatory mediators such as cytokines and chemokines (G-CSF, GM-CSF, IL-1α, IL1β, IL-6, IL-8, and CCL5) by epithelial cells, signal the recruitment of phagocytic cells, including neutrophils, macrophages and dendritic cells (DCs) to the site of infection [109][110][111][112][113][114]. Several comprehensive reviews on C. albicans and host cells and the immune response during C. albicans mucosal infection were recently published [27,108,115]. Here, we focus on highlighting oral local innate immune defenses that play a crucial role in maintaining Candida in its commensal state in the oral cavity.…”

The Regulatory Proteins Rtg1/3 Govern Sphingolipid Homeostasis in the Human-Associated Yeast Candida albicans

“…The EasySep TM Human Neutrophil Enrichment Kit (StemCell Technologies, Inc.) was used to isolate human neutrophils from whole blood of healthy donors (kindly provided by the Department of Transfusion Medicine, University Hospital W€ urzburg) following the supplier's protocol. The neutrophil killing assay was carried out as reported (Meir et al, 2018). Briefly, 7 3 10 5 neutrophils were seeded in supplemented RPMI 1640 medium (2% human serum) in 24-well plates.…”

Transcriptional Circuits Regulating Developmental Processes in Candida albicans

“…Of the 153 direct target genes in this network that are upregulated during GI colonization and disseminated infection, 108 of them are bound by the Rtg1/3 heterodimer (Peŕez et al, 2013), highlighting the central role that Rtg1/3 plays in this network. We note that a subsequent study by the same group identified five transcriptional regulators that influence fitness in an oropharyngeal candidiasis model (Cup9, Zcf8, Zcf21, Zcf27, and Orf19.217), and identified a set of genes that are differentially regulated in response to deletion of CUP9 (Meir et al, 2018). We did not include these data in our analyses since binding experiments that would be necessary to integrate these additional regulators into the commensal-pathogen transcriptional circuit have not been performed.…”