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Research Article | Therapeutics and Prevention

Repurposing Pilocarpine Hydrochloride for Treatment of Candida albicans Infections

Christopher Nile, Monica Falleni, Daniela Cirasola, Abeer Alghamdi, Oliver F. Anderson, Christopher Delaney, Gordon Ramage, Emerenziana Ottaviano, Delfina Tosi, Gaetano Bulfamante, Giulia Morace, Elisa Borghi
J. Andrew Alspaugh, Editor
Christopher Nile
aOral Sciences Research Group, University of Glasgow Dental School, School of Medicine, Dentistry and Nursing, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom
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Monica Falleni
bDivision of Human Pathology, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy
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Daniela Cirasola
cLaboratory of Microbiology, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy
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Abeer Alghamdi
aOral Sciences Research Group, University of Glasgow Dental School, School of Medicine, Dentistry and Nursing, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom
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Oliver F. Anderson
aOral Sciences Research Group, University of Glasgow Dental School, School of Medicine, Dentistry and Nursing, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom
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Christopher Delaney
aOral Sciences Research Group, University of Glasgow Dental School, School of Medicine, Dentistry and Nursing, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom
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Gordon Ramage
aOral Sciences Research Group, University of Glasgow Dental School, School of Medicine, Dentistry and Nursing, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom
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Emerenziana Ottaviano
cLaboratory of Microbiology, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy
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Delfina Tosi
bDivision of Human Pathology, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy
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Gaetano Bulfamante
bDivision of Human Pathology, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy
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Giulia Morace
cLaboratory of Microbiology, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy
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Elisa Borghi
cLaboratory of Microbiology, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy
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J. Andrew Alspaugh
Duke University Medical Center
Roles: Editor
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DOI: 10.1128/mSphere.00689-18
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ABSTRACT

Acetylcholine modulates the virulence of Candida albicans and regulates an appropriate immune response to infection in a Galleria mellonella infection model. Indeed, the evidence suggests that C. albicans possesses a functional cholinergic receptor that can regulate filamentous growth and biofilm formation. Furthermore, G. mellonella immune cell subsets possess repertories of cholinergic receptors which regulate an effective and appropriate cellular immune response to C. albicans infection. This study aimed to investigate the cholinergic receptor subtype involved in regulation of filamentous growth and biofilm formation by C. albicans and determine the roles of cholinergic receptors in modulation of G. mellonella immune cell subsets. The general muscarinic receptor agonist, pilocarpine hydrochloride, inhibited C. albicans biofilm formation and pathogenicity, a phenomenon that could be reversed using the general muscarinic receptor antagonist, scopolamine. Pilocarpine hydrochloride protected G. mellonella larvae from C. albicans infection via inhibition of C. albicans filamentation and appropriate regulation of cellular immunity. However, scopolamine abrogated the capacity of pilocarpine hydrochloride to protect G. mellonella larvae from C. albicans infection. Furthermore, acetylcholine and pilocarpine hydrochloride exhibited differential modulatory capabilities on Galleria mellonella hemocyte responses to C. albicans. The data in this article demonstrate that a muscarinic receptor modulates C. albicans filamentation and biofilm formation. Furthermore, the results suggest that G. mellonella 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.

IMPORTANCE Candida albicans 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. C. albicans infections are combatted by the host immune system. However, Candida 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 C. albicans 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.

  • Copyright © 2019 Nile et al.

This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

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Repurposing Pilocarpine Hydrochloride for Treatment of Candida albicans Infections
Christopher Nile, Monica Falleni, Daniela Cirasola, Abeer Alghamdi, Oliver F. Anderson, Christopher Delaney, Gordon Ramage, Emerenziana Ottaviano, Delfina Tosi, Gaetano Bulfamante, Giulia Morace, Elisa Borghi
mSphere Jan 2019, 4 (1) e00689-18; DOI: 10.1128/mSphere.00689-18

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Repurposing Pilocarpine Hydrochloride for Treatment of Candida albicans Infections
Christopher Nile, Monica Falleni, Daniela Cirasola, Abeer Alghamdi, Oliver F. Anderson, Christopher Delaney, Gordon Ramage, Emerenziana Ottaviano, Delfina Tosi, Gaetano Bulfamante, Giulia Morace, Elisa Borghi
mSphere Jan 2019, 4 (1) e00689-18; DOI: 10.1128/mSphere.00689-18
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KEYWORDS

Candida albicans
Galleria mellonella
biofilm
muscarinic
pilocarpine hydrochloride
repurposing

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