The host immune response to <i>Clostridium difficile</i> infection

Solomon, Katie

doi:10.1177/2049936112472173

Cited by 46 publications

(52 citation statements)

References 157 publications

(206 reference statements)

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“…The direct effects of diet on immune cells have been previously recognized but these effects are closely intertwined with the profound influence of diet to the commensal microbiota as well [ 40 ]. Intestinal dysbiosis is the critical factor in the development of CDI, however, the balance of host anti- and pro-inflammatory responses may define disease severity [ 41 ]. In addition, deficiency of key micronutrients such as zinc have been shown in murine models to both upregulate virulence factors of the pathogen and increase the pro-inflammatory response of the host, leading to worse outcomes [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Defined Nutrient Diets Alter Susceptibility to Clostridium difficile Associated Disease in a Murine Model

et al. 2015

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Background Clostridium difficile is a major identifiable and treatable cause of antibiotic-associated diarrhea. Poor nutritional status contributes to mortality through weakened host defenses against various pathogens. The primary goal of this study was to assess the contribution of a reduced protein diet to the outcomes of C. difficile infection in a murine model.MethodsC57BL/6 mice were fed a traditional house chow or a defined diet with either 20% protein or 2% protein and infected with C. difficile strain VPI10463. Animals were monitored for disease severity, clostridial shedding and fecal toxin levels. Select intestinal microbiota were measured in stool and C. difficile growth and toxin production were quantified ex vivo in intestinal contents from untreated or antibiotic-treated mice fed with the different diets.Results C. difficile infected mice fed with defined diets, particularly (and unexpectedly) with protein deficient diet, had increased survival, decreased weight loss, and decreased overall disease severity. C. difficile shedding and toxin in the stool of the traditional diet group was increased compared with either defined diet 1 day post infection. Mice fed with traditional diet had an increased intestinal Firmicutes to Bacteroidetes ratio following antibiotic exposure compared with either a 2% or 20% protein defined nutrient diet. Ex vivo inoculation of cecal contents from antibiotic-treated mice showed decreased toxin production and C. difficile growth in both defined diets compared with a traditional diet.ConclusionsLow protein diets, and defined nutrient diets in general, were found to be protective against CDI in mice. Associated diet-induced alterations in intestinal microbiota may influence colonization resistance and clostridial toxin production in a defined nutrient diet compared to a traditional diet, leading to increased survival. However, mechanisms which led to survival differences between 2% and 20% protein defined nutrient diets need to be further elucidated.

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Section: Discussionmentioning

confidence: 99%

Defined Nutrient Diets Alter Susceptibility to Clostridium difficile Associated Disease in a Murine Model

et al. 2015

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“…Loss of epithelial integrity results in increased intestinal permeability and the translocation of bacteria from the gut lumen into deeper tissues 118 . In response, resident immune cells and intoxicated epithelial cells release pro-inflammatory cytokines and chemokines that recruit circulating innate and adaptive immune cells and drive the expression of antimicrobial peptides, and the production of reactive nitrogen species (RNS) and reactive oxygen species (ROS) 119,120 (FIG. 4).…”

Section: Host Response To C Difficile Infectionmentioning

confidence: 99%

Clostridium difficile colitis: pathogenesis and host defence

2016

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Clostridium difficile is a major cause of intestinal infection and diarrhoea in individuals following antibiotic treatment. Recent studies have begun to elucidate the mechanisms that induce spore formation and germination and have determined the roles of C. difficile toxins in disease pathogenesis. Exciting progress has also been made in defining the role of the microbiome, specific commensal bacterial species and host immunity in defence against infection with C. difficile. This Review will summarize the recent discoveries and developments in our understanding of C. difficile infection and pathogenesis.

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“…Host responses to infection are increasingly being recognized to play a critical role in CDI outcomes (50). Studies in various knockout as well as aged mice have revealed a crucial role for early innate immune responses in protection against CDI, including neutrophil recruitment, generation of nitric oxide through Nos2, and production of IL-22 and its downstream antimicrobial proteins, including calprotectin proteins (S100a8 and S100a9) and lipocalin-2 (Lcn2) (36, 37, 51-54).…”

Section: Discussionmentioning

confidence: 99%

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

Andersson

Peniche

Galindo

et al. 2020

mBio

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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.

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The host immune response to Clostridium difficile infection

Cited by 46 publications

References 157 publications

Defined Nutrient Diets Alter Susceptibility to Clostridium difficile Associated Disease in a Murine Model

Defined Nutrient Diets Alter Susceptibility to Clostridium difficile Associated Disease in a Murine Model

Clostridium difficile colitis: pathogenesis and host defence

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

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