ABSTRACT Candida albicans, an opportunistic fungal pathogen and the leading cause of hospital-acquired infections, exhibits diverse virulence factors that promote its survival within the human body. The rising incidence of multidrug resistance (MDR) in C. albicans requires urgent development of novel antifungal strategies. Through genetic engineering, our group developed Lectin-Fc(IgG2a) proteins WGA-Fc(IgG2a) and Dectin-1-Fc(IgG2a), which exhibit potent antifungal activity against multiple fungal pathogens and hold promise as broad-spectrum therapeutic agents. In this study, we investigated the direct effects of Lectin-Fc(IgG2a) fusion proteins on C. albicans , uncovering multiple mechanisms that compromise fungal viability. Notably, these antibody-like structures were only partially degraded by secreted aspartyl proteases (Saps) in vitro , as sap mutants exhibited increased susceptibility to growth inhibition. These proteins decreased key fungal cell wall polysaccharides, induced oxidative stress, and disrupted yeast intracellular micronutrient and lipid homeostasis. Furthermore, Lectin-Fc(IgG2a) treatment impaired secretory pathways and significantly reduced the release of extracellular vesicles. Proteomic analysis revealed marked changes in the protein expression profiles of C. albicans , including the enhanced expression of proteins related to stress response and metabolic shift. Moreover, Lectin-Fc(IgG2a) opsonization enhanced dendritic cell activation, contributing to fungal killing. Collectively, these findings support the antifungal direct effects and therapeutic potential of Lectin-Fc(IgG2a) proteins. In addition to their antibody-like functions, they alter fungal morphological features and induce oxidative and metabolic stress, increasing the susceptibility of their cell wall to host immune recognition and clearance. IMPORTANCE Candida albicans is a major cause of life-threatening infections, particularly in hospitalized and immunocompromised individuals, and is increasingly resistant to available antifungal drugs. This study described the effects of a novel immunotherapeutic strategy using genetically engineered antibody-like fusion proteins—Lectin-Fc(IgG2a)—that directly impact fungal growth, disrupt cell wall integrity, induce oxidative stress, and suppress extracellular vesicle production, while also boosting immune cell activation. By targeting multiple fungal vulnerabilities simultaneously, these fusion proteins offer a promising alternative to traditional antifungals as demonstrated in vivo in previous reports by our group, with potential to reshape antifungal therapy and address the global threat of drug-resistant fungal infections.
Mendoza et al. (Thu,) studied this question.