RGD Reference Report - New Host-Directed Therapeutics for the Treatment of Clostridioides difficile Infection. - Rat Genome Database

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New Host-Directed Therapeutics for the Treatment of Clostridioides difficile Infection.

Authors: Andersson, Jourdan A  Peniche, Alex G  Galindo, Cristi L  Boonma, Prapaporn  Sha, Jian  Luna, Ruth Ann  Savidge, Tor C  Chopra, Ashok K  Dann, Sara M 
Citation: Andersson JA, etal., mBio. 2020 Mar 10;11(2). pii: mBio.00053-20. doi: 10.1128/mBio.00053-20.
RGD ID: 40400894
Pubmed: PMID:32156806   (View Abstract at PubMed)
PMCID: PMC7064747   (View Article at PubMed Central)
DOI: DOI:10.1128/mBio.00053-20   (Journal Full-text)

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.IMPORTANCEClostridioides 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.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
IL33HumanClostridium difficile colitis severityISOIl33 (Mus musculus) RGD 
IL33HumanClostridium difficile colitis treatmentISOIl33 (Mus musculus) RGD 
Il33RatClostridium difficile colitis severityISOIl33 (Mus musculus) RGD 
Il33RatClostridium difficile colitis treatmentISOIl33 (Mus musculus) RGD 
Il33MouseClostridium difficile colitis severityIMP  RGD 
Il33MouseClostridium difficile colitis treatmentIEP  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Il33  (interleukin 33)

Genes (Mus musculus)
Il33  (interleukin 33)

Genes (Homo sapiens)
IL33  (interleukin 33)


Additional Information