From Attachment to Damage: Defined Genes of Candida albicans Mediate Adhesion, Invasion and Damage during Interaction with Oral Epithelial Cells

Abstract

Candida albicans frequently causes superficial infections by invading and damaging epithelial cells, but may also cause systemic infections by penetrating through epithelial barriers. C. albicans is an unusual pathogen because it can invade epithelial cells via two distinct mechanisms: induced endocytosis, analogous to facultative intracellular enteropathogenic bacteria, and active penetration, similar to plant pathogenic fungi. Here we investigated the molecular basis of C. albicans epithelial interactions. By systematically assessing the contributions of defined fungal pathways and factors to different stages of epithelial interactions, we provide an expansive portrait of the processes and activities involved in epithelial infection. We strengthen the concept that hyphal formation is critical for epithelial invasion. Importantly, our data support a model whereby initial epithelial invasion per se does not elicit host damage, but that C. albicans relies on a combination of contact-sensing, directed hyphal extension, active penetration and the expression of novel pathogenicity factors for further inter-epithelial invasion, dissemination and ultimate damage of host cells. Finally, we explore the transcriptional landscape of C. albicans during the early stages of epithelial interaction, and, via genetic analysis, identify ICL1 and PGA34 as novel oral epithelial pathogenicity factors.

Candida albicansdimorphism as a therapeutic target

“…Moderate High [36,39,40] Damage None High [40,86] Dissemination Within the bloodstream Across epithelial barriers; interepithelial [18,22,36,46] Iron acquisition via ferritin…”

“…Invasion of C. albicans into epithelial cells is mediated by two distinct processes: induced endocytosis and active penetration [36,39,40]. Induced endocytosis is a host-driven process triggered predominantly by interaction between the C. albicans invasin, Als3, and host E-cadherin.…”

“…In contrast, active penetration is an exclusively fungal-driven process that is mediated by hyphal extension (controlled by Ume6 and Eed1) and hyphal-associated activities such as the production of secreted aspartic proteases (Sap4-6) [35,39,40,44]. Extending hyphae are also essential for interepithelial dissemination: the penetration into adjacent epithelial cells following initial epithelial invasion.…”

The role of pattern recognition receptors in the innate recognition ofCandida albicans

“…1,6 C. albicans is a commensal fungus that colonize on gastrointestinal/genital mucosa of mammalians without causing disease in most healthy individuals, but in case the host defense is weakened under certain circumstances can C. albicans become pathogenic. [7][8][9][10] C. albicans may cause 2 types of infections: superficial infections (such as oral or vaginal candidiasis), and systemic infections (such as life-threatening bloodstream infections/candidaemia). 11 Polymorphological transition is the widely known virulence trait of C. albicans, 12 and the fungus can grow as whitephase yeast cells, GUT cells, opaque-phase cells, gray-phase cells, 13 chlamydospores, ture hyphae, and pseudohyphae.…”

“…15 Yeast-to-hypha transition usually indicates a pathogenic status. 8,16 In accordance, the yeast form is tolerated by the host immune system, while the invasive hyphal form may induce robust immune responses. 17 The cell wall of C. albicans provides targets for host immune system to sense the pathogen and trigger immune response.…”