Inhibiting roles of farnesol and HOG in morphological switching of Candida albicans.

Am J Transl Res 2020;12(11):6988-7001 www.ajtr.org /ISSN:1943-8141/AJTR0110003 Review Article Inhibiting roles of farnesol and HOG in morphological switching of Candida albicans Xueting Wang1*, Hong He1,2, Jiamei Liu3*, Shangfeng Xie1, Jianxin Han4 The Affiliated Hospital of Stomatology, School of Stomatology, Zhejiang University, School of Medicine, 395 Yan’an Road, Hangzhou 310006, Zhejiang, China; 2Key Laboratory of Oral Biomedical Research of Zhejiang Province, Hangzhou 310020, Zhejiang, China; 3Zhejiang Hospital, Hangzhou 310013, Zhejiang, China; 4 Department of Food Science and Nutrition, School of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou 310012, Zhejiang, China. *Co-first authors. 1 Received February 28, 2020; Accepted July 18, 2020; Epub November 15, 2020; Published November 30, 2020 Abstract: Candida albicans is a major opportunistic fungal pathogen of humans, especially in the oral cavity it involves in precancerous lesions. Numerous transcriptional regulators and hypha-specific genes involved in the morphogenesis mechanisms have been identified. Its virulence is predominantly attributed to the potentiality of morphological switching from yeast and pseudohyphae to hyphal growth. Giving attention in farnesol for prevention or intervention of its virulence sense and possible etiologic role in some uncovered premalignant diseases, in addition, to be a quorum-sensing signal molecule and relationship with HOG pathway, although its morphological switching inhibiting function has attracted high attention and got great progress in being elucidated, their exact mode of action is not completely understood. This report provides a review of characteristic aspects of farnesol signaling and HOG pathway during hyphal development. It also includes other associated pathways, molecules, and novel drug development based on the latest researches over the last decade. Furthermore, farnesol as immunomodulatory to host is an important inferring. Keywords: Morphological switching, inhibitor, farnesol, HOG pathway, Candida albicans, dimorphic switch, immune modulation Introduction Human’s opportunistic pathogen Candida albicans (C. albicans) is involved in superficial and systemic diseases such as mucosal premalignant disorders in some population and lifethreatening disseminated invasive infections in susceptible individuals [1]. And its yeastto-hyphal transition and biofilm formation are the predominant virulence-associated traits. Now due to the contribution of some extensive investigations and detailed demonstrations [2-5] about environmental sensing regulation of morphological switching in C. albicans, as well as the development of molecular genetic technologies and the first genome declaration in the world, people have come to further recognize its special dimorphism virulence, which is proposed as an etiologic and therapeutic target [6]. Also, numerous key transcriptional regulators and hypha-specific genes (HSGs) involved in the morphogenesis mechanisms have been identified. The morphological switching of C. albicans includes hyphal initiation, hyphal maintenance, and hypha-to-yeast transition, and its regulatory mechanisms remain in focus [7]. As the drug resistance of fungal or bacteria increases gradually, the research on these mechanisms is conducive to the development of novel antibacterial agents or antibacterial adjuvants. The first identified quorum sensing molecule (QSM) farnesol [8] and HOG (high osmolarity and glycerol) pathway [9], as the morphological switching inhibitors, have attracted high attention and achieved great progress [10, 11], their exact mode of action is not completely understood. Here we review the characteristical aspects of farnesol signaling and HOG pathway during hyphal development, as well as the recently acknowledged other associated path- Farnesol and HOG pathway in C. Albicans ways and molecules. Besides, we also reviewed their related applications and the research progresses in antifungal therapy. Farnesol, a complex role in quorum sensing and switching inhibitor Quorum sensing molecules allow micro-organisms to monitor their growth and control cell density-dependent phenomena. Studies on the roles of farnesol in C. albicans have made progress. Farnesol is secreted by C. albicans white cells only whereas opaque and anaerobic cells turn off farnesol synthesis [4], as a side product of the ergosterol biosynthesis pathway by dephosphorylation of farnesol pyrophosphate, primarily mediated by the pyrophosphatase Dpp3 and C. albicans produces high amounts of farnesol [10, 12]. Farnesol inhibits filamentation [12] including and hyphal initiation [5] and filamentous-growth [3, 4] without disrupting growth rate. Farnesol blocks the yeast-to-hypha transition at least for a period of 6-10 h after germ tube formation but does not block preexisting hyphal elongation [13]. Farnesol plays an additional role in protecting fungus against oxidative stress [14] and immune modulation [12]. Furthermore, several signaling pathways and molecules are involved in farnesol-mediated mechanisms (Figure 1). Inhibiting the Ras1-Cyr1/cAMP-PKA signal pathway The inhibitory function of farnesol on the Ras1Cyr1/cAMP-PKA cascade [3, 12] is well investigated. Ras1p has an advantage of localizing to the membrane and interact with farnesol [15]. The catalytic domain (leucine-rich repeat, LRR) of adenylate cyclase (Cyr1), which once bounds to peptidoglycans will result in filamentation, makes Cyr1p as the central molecular sensor [16]. Therefore, both Ras1p and Cyr1p can be a sensor of farnesol. Farnesol promotes the cleavage of Ras1, resulting in a soluble Ras1 form with a reduced ability to activate Cyr1 [17], and interacts with Ras1 to form a farnesylated Ras1 protein [18]. Furthermore, farnesol directly inhibits Cyr1 activity by binding to the cyclase domain of Cyr1, disturbing cAMP signaling, thus farnesol represses filamentation and supports the hypha-to-yeast transition [17]. The supplementation of exogenous cAMP into media containing farnesol completely restored filamentation [3, 19]. Cyr1 can inte- 6989 grate a diverse range of external signals [20], generating a pulse of cAMP essential for hyphal initiation. Studies by Lu et al. [21] indicated the activation of the cAMP-dependent protein kinase A (PKA) pathway was required to downregulate the transcription of NRG1 during hyphal growth as Nrg1 protein level did not show an obvious reduction in cyr1 and tpk2 mutants. Tpk1 and Tpk2 are PKA catalytic subunits, and deletion mutants of TPK2 block hyphal formation [22, 23]. The mutants lacking pde2 showed increased cAMP signaling and more resistant to farnesol-mediated induction of hypha-to-yeast transitions [24]. CYR1 and PDE2 regulate a pair of enzymes associated with cAMP synthesis and degradation, and PDE2 regulation by farnesol was subordinate to CYR1 regulation [25]. In addition, farnesol can induce hydrogen peroxide resistance. S (...truncated)