Repurposing Pilocarpine Hydrochloride for Treatment of Candida albicans Infections

Abstract

Acetylcholine modulates the virulence of <i>Candida</i><i>albicans</i> and regulates an appropriate immune response to infection in a <i>Galleria mellonella</i> infection model. Indeed, the evidence suggests that <i>C. albicans</i> possesses a functional cholinergic receptor that can regulate filamentous growth and biofilm formation. Furthermore, <i>G. mellonella</i> immune cell subsets possess repertories of cholinergic receptors which regulate an effective and appropriate cellular immune response to <i>C. albicans</i> infection. This study aimed to investigate the cholinergic receptor subtype involved in regulation of filamentous growth and biofilm formation by <i>C. albicans</i> and determine the roles of cholinergic receptors in modulation of <i>G. mellonella</i> immune cell subsets. The general muscarinic receptor agonist, pilocarpine hydrochloride, inhibited <i>C. albicans</i> biofilm formation and pathogenicity, a phenomenon that could be reversed using the general muscarinic receptor antagonist, scopolamine. Pilocarpine hydrochloride protected <i>G. mellonella</i> larvae from <i>C. albicans</i> infection via inhibition of <i>C. albicans</i> filamentation and appropriate regulation of cellular immunity. However, scopolamine abrogated the capacity of pilocarpine hydrochloride to protect <i>G. mellonella</i> larvae from <i>C. albicans</i> infection. Furthermore, acetylcholine and pilocarpine hydrochloride exhibited differential modulatory capabilities on <i>Galleria mellonella</i> hemocyte responses to <i>C. albicans</i> The data in this article demonstrate that a muscarinic receptor modulates <i>C. albicans</i> filamentation and biofilm formation. Furthermore, the results suggest that <i>G. mellonella</i> hemocyte subsets possess unique repertoires of cholinergic receptors that regulate their differentiation, activation, and function in contrasting manners. Therefore, targeting cholinergic receptors by repurposing currently licensed cholinergic drugs may offer novel therapeutic solutions for the prevention or treatment of fungal infections.<b>IMPORTANCE</b><i>Candida albicans</i> is the most common human fungal pathogen with an estimated crude mortality rate of 40%. The ability of the organism to switch from the yeast to hyphal form and produce biofilms are important virulence factors. <i>C. albicans</i> infections are combatted by the host immune system. However, <i>Candida</i> triggers a strong inflammatory response that, if not appropriately regulated, can damage host tissues. Therefore, it is important that the host immune response eliminates the fungus but limits tissue damage. This study provides evidence that targeting cholinergic receptors cannot only curb the virulence of <i>C. albicans</i> by inhibiting filamentous growth and biofilm formation but can also appropriately regulate the host immune response to induce rapid clearance with limited damage to vital tissues. This article provides evidence that repurposing licensed drugs that target cholinergic receptors may offer novel therapeutic solutions for the prevention or treatment of fungal infections.