New Host-Directed Therapeutics for the Treatment of <named-content content-type="genus-species">Clostridioides difficile</named-content> Infection

ABSTRACT Frequent and excessive use of antibiotics primes patients to Clostridioides difficile infection (CDI), which leads to fatal pseudomembranous colitis, with limited treatment options. In earlier reports, we used a drug repurposing strategy and identified amoxapine (an antidepressant), doxapra...

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Autores principales:	Jourdan A. Andersson, Alex G. Peniche, Cristi L. Galindo, Prapaporn Boonma, Jian Sha, Ruth Ann Luna, Tor C. Savidge, Ashok K. Chopra, Sara M. Dann
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	Clostridioides difficile germfree mice host-directed therapeutics mechanism of action microbiota mouse model of infection Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/5e714ff007e247f187ae4679e2689807
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spelling	oai:doaj.org-article:5e714ff007e247f187ae4679e26898072021-11-15T15:57:02ZNew Host-Directed Therapeutics for the Treatment of <named-content content-type="genus-species">Clostridioides difficile</named-content> Infection10.1128/mBio.00053-202150-7511https://doaj.org/article/5e714ff007e247f187ae4679e26898072020-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00053-20https://doaj.org/toc/2150-7511ABSTRACT Frequent and excessive use of antibiotics primes patients to Clostridioides difficile infection (CDI), which leads to fatal pseudomembranous colitis, with limited treatment options. In earlier reports, we used a drug repurposing strategy and identified amoxapine (an antidepressant), doxapram (a breathing stimulant), and trifluoperazine (an antipsychotic), which provided significant protection to mice against lethal infections with several pathogens, including C. difficile. However, the mechanisms of action of these drugs were not known. Here, we provide evidence that all three drugs offered protection against experimental CDI by reducing bacterial burden and toxin levels, although the drugs were neither bacteriostatic nor bactericidal in nature and had minimal impact on the composition of the microbiota. Drug-mediated protection was dependent on the presence of the microbiota, implicating its role in evoking host defenses that promoted protective immunity. By utilizing transcriptome sequencing (RNA-seq), we identified that each drug increased expression of several innate immune response-related genes, including those involved in the recruitment of neutrophils, the production of interleukin 33 (IL-33), and the IL-22 signaling pathway. The RNA-seq data on selected genes were confirmed by quantitative real-time PCR (qRT-PCR) and protein assays. Focusing on amoxapine, which had the best anti-CDI outcome, we demonstrated that neutralization of IL-33 or depletion of neutrophils resulted in loss of drug efficacy. Overall, our lead drugs promote disease alleviation and survival in the murine model through activation of IL-33 and by clearing the pathogen through host defense mechanisms that critically include an early influx of neutrophils. IMPORTANCE Clostridioides difficile is a spore-forming anaerobic bacterium and the leading cause of antibiotic-associated colitis. With few therapeutic options and high rates of disease recurrence, the need to develop new treatment options is urgent. Prior studies utilizing a repurposing approach identified three nonantibiotic Food and Drug Administration-approved drugs, amoxapine, doxapram, and trifluoperazine, with efficacy against a broad range of human pathogens; however, the protective mechanisms remained unknown. Here, we identified mechanisms leading to drug efficacy in a murine model of lethal C. difficile infection (CDI), advancing our understanding of the role of these drugs in infectious disease pathogenesis that center on host immune responses to C. difficile. Overall, these studies highlight the crucial involvement of innate immune responses, as well as the importance of immunomodulation as a potential therapeutic option to combat CDI.Jourdan A. AnderssonAlex G. PenicheCristi L. GalindoPrapaporn BoonmaJian ShaRuth Ann LunaTor C. SavidgeAshok K. ChopraSara M. DannAmerican Society for MicrobiologyarticleClostridioides difficilegermfree micehost-directed therapeuticsmechanism of actionmicrobiotamouse model of infectionMicrobiologyQR1-502ENmBio, Vol 11, Iss 2 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Clostridioides difficile germfree mice host-directed therapeutics mechanism of action microbiota mouse model of infection Microbiology QR1-502
spellingShingle	Clostridioides difficile germfree mice host-directed therapeutics mechanism of action microbiota mouse model of infection Microbiology QR1-502 Jourdan A. Andersson Alex G. Peniche Cristi L. Galindo Prapaporn Boonma Jian Sha Ruth Ann Luna Tor C. Savidge Ashok K. Chopra Sara M. Dann New Host-Directed Therapeutics for the Treatment of <named-content content-type="genus-species">Clostridioides difficile</named-content> Infection
description	ABSTRACT Frequent and excessive use of antibiotics primes patients to Clostridioides difficile infection (CDI), which leads to fatal pseudomembranous colitis, with limited treatment options. In earlier reports, we used a drug repurposing strategy and identified amoxapine (an antidepressant), doxapram (a breathing stimulant), and trifluoperazine (an antipsychotic), which provided significant protection to mice against lethal infections with several pathogens, including C. difficile. However, the mechanisms of action of these drugs were not known. Here, we provide evidence that all three drugs offered protection against experimental CDI by reducing bacterial burden and toxin levels, although the drugs were neither bacteriostatic nor bactericidal in nature and had minimal impact on the composition of the microbiota. Drug-mediated protection was dependent on the presence of the microbiota, implicating its role in evoking host defenses that promoted protective immunity. By utilizing transcriptome sequencing (RNA-seq), we identified that each drug increased expression of several innate immune response-related genes, including those involved in the recruitment of neutrophils, the production of interleukin 33 (IL-33), and the IL-22 signaling pathway. The RNA-seq data on selected genes were confirmed by quantitative real-time PCR (qRT-PCR) and protein assays. Focusing on amoxapine, which had the best anti-CDI outcome, we demonstrated that neutralization of IL-33 or depletion of neutrophils resulted in loss of drug efficacy. Overall, our lead drugs promote disease alleviation and survival in the murine model through activation of IL-33 and by clearing the pathogen through host defense mechanisms that critically include an early influx of neutrophils. IMPORTANCE Clostridioides difficile is a spore-forming anaerobic bacterium and the leading cause of antibiotic-associated colitis. With few therapeutic options and high rates of disease recurrence, the need to develop new treatment options is urgent. Prior studies utilizing a repurposing approach identified three nonantibiotic Food and Drug Administration-approved drugs, amoxapine, doxapram, and trifluoperazine, with efficacy against a broad range of human pathogens; however, the protective mechanisms remained unknown. Here, we identified mechanisms leading to drug efficacy in a murine model of lethal C. difficile infection (CDI), advancing our understanding of the role of these drugs in infectious disease pathogenesis that center on host immune responses to C. difficile. Overall, these studies highlight the crucial involvement of innate immune responses, as well as the importance of immunomodulation as a potential therapeutic option to combat CDI.
format	article
author	Jourdan A. Andersson Alex G. Peniche Cristi L. Galindo Prapaporn Boonma Jian Sha Ruth Ann Luna Tor C. Savidge Ashok K. Chopra Sara M. Dann
author_facet	Jourdan A. Andersson Alex G. Peniche Cristi L. Galindo Prapaporn Boonma Jian Sha Ruth Ann Luna Tor C. Savidge Ashok K. Chopra Sara M. Dann
author_sort	Jourdan A. Andersson
title	New Host-Directed Therapeutics for the Treatment of <named-content content-type="genus-species">Clostridioides difficile</named-content> Infection
title_short	New Host-Directed Therapeutics for the Treatment of <named-content content-type="genus-species">Clostridioides difficile</named-content> Infection
title_full	New Host-Directed Therapeutics for the Treatment of <named-content content-type="genus-species">Clostridioides difficile</named-content> Infection
title_fullStr	New Host-Directed Therapeutics for the Treatment of <named-content content-type="genus-species">Clostridioides difficile</named-content> Infection
title_full_unstemmed	New Host-Directed Therapeutics for the Treatment of <named-content content-type="genus-species">Clostridioides difficile</named-content> Infection
title_sort	new host-directed therapeutics for the treatment of <named-content content-type="genus-species">clostridioides difficile</named-content> infection
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/5e714ff007e247f187ae4679e2689807
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New Host-Directed Therapeutics for the Treatment of <named-content content-type="genus-species">Clostridioides difficile</named-content> Infection

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