Host-Pathogen Interactions in Candida albicans Infections

Candida albicans is a commensal fungus that inhabits the human mucosa but can shift to a pathogenic state under immune compromise or barrier disruption. This transition involves a morphological switch from yeast to filamentous hyphae, enabling tissue invasion, host-cell damage and dissemination. Central to C. albicans pathogenesis is the secretion of candidalysin, a peptide toxin that perforates epithelial and phagocyte membranes, activates danger-signalling pathways and modulates immune responses. Host recognition of fungal cell-wall components and candidalysin engages pattern-recognition receptors, such as Toll-like receptors and the NLRP3 inflammasome, leading to cytokine release, neutrophil recruitment and barrier repair. Epithelial cells contribute to defence by initiating biphasic MAPK signalling and maintaining cell-cell junctions via NF-κB-dependent pathways. Phagocytes deploy oxidative and non-oxidative mechanisms, yet hyphal growth and candidalysin can trigger inflammasome-dependent pyroptosis and inflammasome-independent cytolysis, facilitating fungal escape. Nutrient acquisition, notably zinc uptake, influences fungal fitness and barrier penetration. Translocation across the intestinal epithelium is a stepwise process of invasion, toxin-mediated damage and loss of integrity, underpinning bloodstream invasion. Understanding the dynamic interplay between fungal virulence factors and host defence circuits is critical for developing targeted therapies against mucosal and systemic candidiasis.

Research from Nature Portfolio

A recent high-throughput interactome study has mapped the network of human proteins targeted by each of the eight Ece1 peptides, revealing that candidalysin binds directly to the cyclin-activating kinase subunit CCNH. This interaction impairs DNA damage repair, promoting double-strand breaks and enhancing fungal persistence in oropharyngeal models. Mechanistic insights indicate that candidalysin hijacks the host cell’s repair machinery to create a niche for infection. Foundational work on the NLRP3 inflammasome has demonstrated that candidalysin is a dual-function effector, both activating caspase-1 via potassium efflux and causing direct cytolysis of macrophages and dendritic cells through a membrane-piercing mechanism. These findings establish candidalysin as a central modulator of both epithelial and innate immune responses, linking toxin activity to immune evasion and tissue damage.

Host-Pathogen Interactions in Candida albicans Infections publication trend

The graph below shows the total number of articles in host-pathogen interactions in candida albicans infections across all publications each year (not limited to Nature Index journals).

Technical terms

Candidalysin: A cytolytic peptide toxin secreted by C. albicans hyphae that disrupts host-cell membranes and triggers immune signalling.

Hyphae: Filamentous, invasive form of C. albicans that enables tissue penetration and toxin secretion.

Inflammasome: A multiprotein cytosolic complex in innate immune cells that activates caspase-1 and drives inflammatory cell death.

NF-κB: A transcription factor family central to regulating immune and inflammatory responses in epithelial and immune cells.

Translocation: The process by which C. albicans crosses epithelial barriers, typically via toxin-mediated damage and junctional disruption to enter the bloodstream.

References

1. Global fungal-host interactome mapping identifies host targets of candidalysin. Nature Communications (2024).
2. Candida albicans translocation through the intestinal epithelial barrier is promoted by fungal zinc acquisition and limited by NFκB-mediated barrier protection. PLOS Pathogens (2024).
3. Nanobody-mediated neutralization of candidalysin prevents epithelial damage and inflammatory responses that drive vulvovaginal candidiasis pathogenesis. mBio (2024).
4. EGR1 regulates oral epithelial cell responses to Candida albicans via the EGFR- ERK1/2 pathway. Virulence (2024).
5. A Biphasic Innate Immune MAPK Response Discriminates between the Yeast and Hyphal Forms of Candida albicans in Epithelial Cells. Cell Host & Microbe (2010).
6. The fungal peptide toxin Candidalysin activates the NLRP3 inflammasome and causes cytolysis in mononuclear phagocytes. Nature Communications (2018).
7. Candida albicans-Induced Epithelial Damage Mediates Translocation through Intestinal Barriers. mBio (2018).
8. Candidalysin: discovery and function in Candida albicans infections. Current Opinion in Microbiology (2019).