The Dual Function of the Fungal Toxin Candidalysin during Candida albicans-Macrophage Interaction and Virulence.

Annika König,Lydia Kasper,Bernhard Hube

doi:10.3390/toxins12080469

Abstract

The dimorphic fungus Candida albicans is both a harmless commensal organism on mucosal surfaces and an opportunistic pathogen. Under certain predisposing conditions, the fungus can overgrow the mucosal microbiome and cause both superficial and life-threatening systemic infections after gaining access to the bloodstream. As the first line of defense of the innate immune response, infecting C. albicans cells face macrophages, which mediate the clearance of invading fungi by intracellular killing. However, the fungus has evolved sophisticated strategies to counteract macrophage antimicrobial activities and thus evade immune surveillance. The cytolytic peptide toxin, candidalysin, contributes to this fungal defense machinery by damaging immune cell membranes, providing an escape route from the hostile phagosome environment. Nevertheless, candidalysin also induces NLRP3 inflammasome activation, leading to an increased host-protective pro-inflammatory response in mononuclear phagocytes. Therefore, candidalysin facilitates immune evasion by acting as a classical virulence factor but also contributes to an antifungal immune response, serving as an avirulence factor. In this review, we discuss the role of candidalysin during C. albicans infections, focusing on its implications during C. albicans-macrophage interactions.

Highlights

Of the estimated three to five million fungal species existing worldwide, only a tiny portion cause infections in a human host [1,2]
The data suggest that production of candidalysin, rather than hypha formation per se or secreted hydrolases, are the main mediators of the host cell damage caused by C. albicans [74]
Candidalysin has recently been identified as one major trigger of hypha-dependent NOD-like receptor protein 3 (NLRP3) inflammasome activation in primary human macrophages and murine dendritic cells [78,94]

Summary

Introduction

Of the estimated three to five million fungal species existing worldwide, only a tiny portion (less than 0.01%) cause infections in a human host [1,2]. C. albicans evades the acidic phagosomal environment; Candida-containing phagosomes change from acidic to neutral pH over time [45] This phagosome neutralization is likely mediated by fungal activities such as the production of neutralizing metabolites [46] or phagosome damage by extending fungal hyphae, which leads to proton leakage [45]. Escaping hyphae consume glucose in the environment rapidly, which provides a third pathway for C. albicans-induced macrophage cell death [57]. In combination, these adaptation mechanisms are thought to promote C. albicans survival and even proliferation inside macrophages and allow escape from these immune cells

Candidalysin—A Hypha-Specific Cytolytic Peptide Toxin

Dual Function of Candidalysin during Infection

Findings

Conclusions