Candidiasis: Insights into Virulence Factors, Complement Evasion and Antifungal Drug Resistance

Abstract

Invasive fungal infections constitute a substantial global health burden, with invasive candidiasis representing approximately 70% of reported cases worldwide. The emergence of antifungal resistance among Candida species has further exacerbated this challenge to healthcare systems. Recent epidemiological studies have documented a concerning shift towards non-albicans Candida species, exhibiting reduced antifungal susceptibility, in invasive candidiasis cases. The complement system serves as a crucial first-line defence mechanism against Candida infections. These fungal pathogens can activate the complement cascade through three conventional pathways-classical, lectin, and alternative-in addition to activation through the coagulation system. While these pathways are initiated by distinct molecular triggers, they converge at C3 convertase formation, ultimately generating biologically active products and the membrane attack complex. Candida species have evolved sophisticated mechanisms to evade complement-mediated host defence, including the masking of cell wall components, proteolytic cleavage and inhibition of complement proteins, recruitment of complement regulators, and acquisition of host proteins. This review examines the intricate interplay between Candida species and the host complement system, with emphasis on complement evasion strategies. Furthermore, we highlight the importance of exploring the crosstalk between antifungal resistance and immune evasion strategies employed by Candida species. Understanding these interactions may facilitate the development of novel therapeutic approaches and strategies to overcome treatment failures in Candida species infections.

Keywords: Candida species; complement evasion; complement regulators; secreted proteases.

Figure 1

Overview of complement activation pathways and their interactions with the contact, coagulation, and fibrinolytic systems. This figure illustrates how Candida activates the three main complement pathways: classical (left), lectin (middle), and alternative (right). During activation, proteolytic cleavage generates anaphylatoxins (C4a, C3a, and C5a). All three pathways converge at C3 convertase formation, leading to C5 convertase assembly. This results in the generation of the membrane attack complex (MAC). The figure further illustrates how components of the contact system (kallikrein), coagulation system (thrombin, FXIa, FXa, and FIXa), and fibrinolytic system (plasmin) can directly cleave C3 and C5, providing alternative routes of complement activation. Additionally, kallikrein can cleave factor B, initiating the alternative pathway.

Figure 2

Crosstalk between antifungal resistance and immune evasion. This diagram illustrates how adaptations that enable Candida to evade host immune responses can simultaneously contribute to increased antifungal resistance, and vice versa.