Repurposing Pilocarpine Hydrochloride for Treatment of <named-content content-type="genus-species">Candida albicans</named-content> Infections
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 b...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
American Society for Microbiology
2019-02-01
|
| Series: | mSphere |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mSphere.00689-18 |
| _version_ | 1819260498222252032 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Christopher Nile |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-23T19:26:51Z |
| format | Article |
| id | doaj.art-3f781b74dc9b49a396a7f1ff646169e3 |
| institution | Directory Open Access Journal |
| issn | 2379-5042 |
| language | English |
| last_indexed | 2024-12-23T19:26:51Z |
| publishDate | 2019-02-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mSphere |
| spelling | doaj.art-3f781b74dc9b49a396a7f1ff646169e32022-12-21T17:34:01ZengAmerican Society for MicrobiologymSphere2379-50422019-02-014110.1128/mSphere.00689-18Repurposing Pilocarpine Hydrochloride for Treatment of <named-content content-type="genus-species">Candida albicans</named-content> InfectionsChristopher Nile0Monica Falleni1Daniela Cirasola2Abeer Alghamdi3Oliver F. Anderson4Christopher Delaney5Gordon Ramage6Emerenziana Ottaviano7Delfina Tosi8Gaetano Bulfamante9Giulia Morace10Elisa Borghi11Oral 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 KingdomDivision of Human Pathology, Department of Health Sciences, Università degli Studi di Milano, Milan, ItalyLaboratory of Microbiology, Department of Health Sciences, Università degli Studi di Milano, Milan, ItalyOral 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 KingdomOral 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 KingdomOral 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 KingdomOral 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 KingdomLaboratory of Microbiology, Department of Health Sciences, Università degli Studi di Milano, Milan, ItalyDivision of Human Pathology, Department of Health Sciences, Università degli Studi di Milano, Milan, ItalyDivision of Human Pathology, Department of Health Sciences, Università degli Studi di Milano, Milan, ItalyLaboratory of Microbiology, Department of Health Sciences, Università degli Studi di Milano, Milan, ItalyLaboratory of Microbiology, Department of Health Sciences, Università degli Studi di Milano, Milan, ItalyABSTRACT 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.https://journals.asm.org/doi/10.1128/mSphere.00689-18Candida albicansGalleria mellonellabiofilmmuscarinicpilocarpine hydrochloriderepurposing |
| spellingShingle | 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 Repurposing Pilocarpine Hydrochloride for Treatment of <named-content content-type="genus-species">Candida albicans</named-content> Infections mSphere Candida albicans Galleria mellonella biofilm muscarinic pilocarpine hydrochloride repurposing |
| title | Repurposing Pilocarpine Hydrochloride for Treatment of <named-content content-type="genus-species">Candida albicans</named-content> Infections |
| title_full | Repurposing Pilocarpine Hydrochloride for Treatment of <named-content content-type="genus-species">Candida albicans</named-content> Infections |
| title_fullStr | Repurposing Pilocarpine Hydrochloride for Treatment of <named-content content-type="genus-species">Candida albicans</named-content> Infections |
| title_full_unstemmed | Repurposing Pilocarpine Hydrochloride for Treatment of <named-content content-type="genus-species">Candida albicans</named-content> Infections |
| title_short | Repurposing Pilocarpine Hydrochloride for Treatment of <named-content content-type="genus-species">Candida albicans</named-content> Infections |
| title_sort | repurposing pilocarpine hydrochloride for treatment of named content content type genus species candida albicans named content infections |
| topic | Candida albicans Galleria mellonella biofilm muscarinic pilocarpine hydrochloride repurposing |
| url | https://journals.asm.org/doi/10.1128/mSphere.00689-18 |
| work_keys_str_mv | AT christophernile repurposingpilocarpinehydrochloridefortreatmentofnamedcontentcontenttypegenusspeciescandidaalbicansnamedcontentinfections AT monicafalleni repurposingpilocarpinehydrochloridefortreatmentofnamedcontentcontenttypegenusspeciescandidaalbicansnamedcontentinfections AT danielacirasola repurposingpilocarpinehydrochloridefortreatmentofnamedcontentcontenttypegenusspeciescandidaalbicansnamedcontentinfections AT abeeralghamdi repurposingpilocarpinehydrochloridefortreatmentofnamedcontentcontenttypegenusspeciescandidaalbicansnamedcontentinfections AT oliverfanderson repurposingpilocarpinehydrochloridefortreatmentofnamedcontentcontenttypegenusspeciescandidaalbicansnamedcontentinfections AT christopherdelaney repurposingpilocarpinehydrochloridefortreatmentofnamedcontentcontenttypegenusspeciescandidaalbicansnamedcontentinfections AT gordonramage repurposingpilocarpinehydrochloridefortreatmentofnamedcontentcontenttypegenusspeciescandidaalbicansnamedcontentinfections AT emerenzianaottaviano repurposingpilocarpinehydrochloridefortreatmentofnamedcontentcontenttypegenusspeciescandidaalbicansnamedcontentinfections AT delfinatosi repurposingpilocarpinehydrochloridefortreatmentofnamedcontentcontenttypegenusspeciescandidaalbicansnamedcontentinfections AT gaetanobulfamante repurposingpilocarpinehydrochloridefortreatmentofnamedcontentcontenttypegenusspeciescandidaalbicansnamedcontentinfections AT giuliamorace repurposingpilocarpinehydrochloridefortreatmentofnamedcontentcontenttypegenusspeciescandidaalbicansnamedcontentinfections AT elisaborghi repurposingpilocarpinehydrochloridefortreatmentofnamedcontentcontenttypegenusspeciescandidaalbicansnamedcontentinfections |