The role of L-type amino acid transporter 1 in the pathogenicity of Candida albicans

Abstract

Our recent study showed that lat1, which encodes L-type amino acid transporter 1 (Lat1) was centrally positioned in the gene co-expression network of a Candida albicans (C. albicans) infection model of cell culture and suggested that this gene might play a critical role in the pathogenesis of C. albicans infections. In the current work, we used CRISPR-Cas9 to generate a C. albicans lat1 mutant strain (lat1Δ/Δ), using C. albicans SC5314 as the wild-type (WT) strain. An in vitro Candida infection model using vaginal epithelial cells and a murine model of vulvovaginal candidiasis was used to investigate the role of lat1 in the pathogenicity of C. albicans. It was found that lat1 played important roles in cell proliferation, morphogenesis, early adherence, and biofilm formation of C. albicans. VK2-E6E7 human vaginal epithelial cells infected with the lat1Δ/Δ mutant strain also showed significantly lower activation of Toll-like receptor 2/4 (TLR2/4) and the downstream MyD88/NF-κB signaling pathway, accompanied by an attenuated secretion of inflammatory cytokines. In the murine model of vulvovaginal candidiasis, infection caused by lat1Δ/Δ showed a lower fungal burden in the vaginal lavage fluid, reduced production of inflammatory cytokines, and diminished recruitment of neutrophils to the vaginal epithelium, relative to that caused by the WT strain. Based on these findings, we conclude that lat1 plays an important role in the host-pathogen interactions in C. albicans infections by impacting the virulence of C. albicans and host inflammatory responses; the latter was possibly via the TLR2/4-MyD88-NF-κB pathway.IMPORTANCEEffective management of vulvovaginal candidiasis requires a comprehensive understanding of virulence genes in C. albicans and their role in the host-pathogen interactions. Our study identified lat1 as an important virulence factor of C. albicans, impacting fungal adaptations, including morphogenesis and biofilm formation, virulence, and host immune responses, such as the epithelial TLR2/4-MyD88-NF-κB activation in the murine model of vulvovaginal candidiasis. Lat1-mediated amino acid transport may serve as a key metabolic constraint during early infection. Further research is warranted to validate the clinical importance of lat1 in vulvovaginal candidiasis and its potential as a therapeutic target.

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