Regulatory events governing host-C. albicans interaction: potential implications for wound healing

Abstract

Regulatory events governing host-C. albicans interaction: potential implications for wound healing. Candida albicans is an opportunistic fungal pathogen that resides commensally in 50% of the world population and is known to manifest infection in immunocompromised people. Majorly C. albicans causes superficial infections such as vaginal candidiasis, oropharyngeal candidiasis, and open wound colonization. Fungal infections, specifically C. albicans, have been reported to delay wound healing process. Such delayed, insufficient, or disorganized healing process often develops a state of pathological inflammation. Our research has attempted to investigate the mechanisms regulating C. albicans mediated delayed wound healing. PART1: Exploring the role of histone demethylase UTX and transcription factor CREB in Candida albicans-mediated delayed wound healing. Recent studies have underscored a role for epigenetics in modulating inflammatory responses during host-pathogen interactions. Histone modifications like acetylation, methylation, phosphorylation, and ubiquitination play a crucial role in regulating transcriptional activities. Histone lysine methylation plays a key role in regulating various biological processes and has been observed to be regulated by pathogens in the host environment. Histone methyl transferases catalyse the methylation of lysine and arginine residues in histones. Many histone demethylases have recently been identified to act as “erasers” that remove the resident methylation marks from histone residues leading to either gene repression or activation depending on the lysine residue. In this regard, UTX (Ubiquitously Transcribed tetratricopeptide repeat on chromosome X, also known as Kdm6a) is a histone demethylase that removes the di- and tri-methylation marks from histone H3K27 residue. Kdm6a has previously been reported to be upregulated during normal homeostatic wound healing. However, its role in the same has not been well studied. In this regard, we wanted to investigate its role in C. albicans-mediated delayed wound healing. We observe a downregulation of Kdm6a upon C. albicans infection in macrophages, as well as in non-healing C. albicans infected wounds. Our findings indicate that Kdm6a upon C. albicans infection was primarily responsible for repressing the expression of genes involved in promoting wound healing. Next, we were intrigued to identify other key molecular players that might be implicated in contributing to delayed wound healing and enhanced inflammation by C. albicans. In literature, it has been reported that during wound healing, transcription factors orchestrate the dynamic and complex gene expression programmes. CREB, a master transcription regulator, plays numerous roles in immune system functions. CREB is known to modulate the pro-inflammatory immune responses via the activation of NF-KB activity. CREB is also known to differentially regulate Th1, Th2, and Th17 immune responses. Our results have shown that CREB, in its phosphorylated form, regulates the levels of pro-inflammatory cytokines in macrophages upon C. albicans infection as well as genes that are known to delay wound healing. Hence, our study underscores a role of Kdm6a and CREB in C. albicans mediated delayed wound healing. PART2: Understanding the role of a Vitamin A metabolite adapalene during C. albicans mediated delayed wound healing. To counteract fungal pathogenesis, several drugs or antifungal agents have been used to target harmful infections in the host, but they have frequently failed to produce results in controlled clinical trials. The use of vitamins as effective adjuvants in the prevention or reversal of chronic diseases hasn’t been very well explored. To suppress C. albicans infection-induced chronic inflammatory damage to the host, we have attempted to investigate the anti-inflammatory and phagocytic properties of a retinoic acid synthetic metabolite adapalene (ADA) in our current work. It has been previously shown that administration of ADA intraperitoneally to mice with Candida albicans infected wounds, significantly rescued the delayed wound healing phenotype while enhancing an anti-inflammatory response. In our current work, we have identified that ADA regulates the dynamic nature of actin filament assembly in macrophages, which leads to enhanced phagophore formation that may further contribute to increased C. albicans phagocytosis. Administering ADA to macrophages infected with C. albicans resulted in specific suppression of the actin-binding protein cofilin, which significantly increased the macrophage’s capacity to entrap the phagocytosed pathogen. We have, therefore, highlighted the possible therapeutic potential of adapalene as it suppresses exacerbated damage to wound tissue during C. albicans infection while also restoring immune system homeostasis.