Toxin-Mediated Paracellular Transport of Antitoxin Antibodies Facilitates Protection against Clostridium difficile Infection

Zhang, Z.; Chen, X.; Hernandez, Lorraine D.; Lipari, Philip; Flattery, Amy; Chen, S.-C.; Krämer, Susanne; Polishook, Jon D.; Racine, Fred; Cape, H.; Kelly, Ciarán P.; Therien, Alex G.

doi:10.1128/iai.02550-14

Cited by 38 publications

(36 citation statements)

References 41 publications

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“… 58 , 59 A new model of protection against CDI in the gut lumen by systemic antibodies suggests that the transport of antibodies across the gut wall is not solely Fc-dependent but is due in part to the paracellular transport of systemic antibodies following toxin-mediate damage to the gut epithelium. 60 …”

Section: Discussionmentioning

confidence: 99%

Immunogenicity and protective efficacy of recombinant Clostridium difficile flagellar protein FliC

Ghose

Eugenis

Sun

et al. 2016

Emerging Microbes & Infections

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Clostridium difficile is a Gram-positive bacillus and is the leading cause of toxin-mediated nosocomial diarrhea following antibiotic use. C. difficile flagella play a role in colonization, adherence, biofilm formation, and toxin production, which might contribute to the overall virulence of certain strains. Human and animal studies indicate that anti-flagella immune responses may play a role in protection against colonization by C. difficile and subsequent disease outcome. Here we report that recombinant C. difficile flagellin (FliC) is immunogenic and protective in a murine model of C. difficile infection (CDI) against a clinical C. difficile strain, UK1. Passive protection experiments using anti-FliC polyclonal serum in mice suggest this protection to be antibody-mediated. FliC immunization also was able to afford partial protection against CDI and death in hamsters following challenge with C. difficile 630Δerm. Additionally, immunization against FliC does not have an adverse effect on the normal gut flora of vaccinated hamsters as evidenced by comparing the fecal microbiome of vaccinated and control hamsters. Therefore, the use of FliC as a vaccine candidate against CDI warrants further testing.

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Section: Discussionmentioning

confidence: 99%

Immunogenicity and protective efficacy of recombinant Clostridium difficile flagellar protein FliC

Ghose

Eugenis

Sun

et al. 2016

Emerging Microbes & Infections

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“…26,41 Serum antitoxin antibodies bind luminal toxins in CDI by toxin-mediated paracellular transport of both serum IgA and IgG. 42 While there is some risk in interpreting our data given the relatively small sample size, UC patients appear to have a deficit in humoral response with lower levels of toxin A and B IgA at baseline and IBD patients as a group have lowered IgA response against toxin A with new infection but have higher IgA levels against toxin A if previously exposed to CDI compared to their exposure-free counterparts. The significance of this is not yet fully understood but there is data to indicate the importance of IgA anti-toxin responses in improved clinical outcomes in CDI.…”

Section: Discussionmentioning

confidence: 99%

Host Immune Response to Clostridium difficile Infection in Inflammatory Bowel Disease Patients

Hughes

Qazi

Berg

et al. 2016

Inflammatory Bowel Diseases

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Background Clostridium difficile infection affects IBD patients. This study’s aim was to compare humoral response to C. difficile toxins in IBD and control outpatients. Methods We prospectively followed adult IBD and control subjects with serum and stool tested by PCR obtained at enrollment and during periods of CDI. Semi-quantitative serum levels of IgM, IgG and IgA to C. difficile toxins A and B were measured. Results 119 stool and 117 serum samples were obtained from 150 subjects. Different levels of IgA to toxin A (p=0.0016) and toxin B (p=0.0468) were noted between different IBD groups. Toxin A IgA levels were higher in the CD group (p=0.0321) and IPAA group (p=0.001) compared to the UC group and toxin B IgA levels were higher in the IPAA group compared to the UC group (p=0.0309). There were lower levels of toxin A IgA in IBD patients with compared with those in subjects without new CDI (P=0.0488) and higher levels in IBD patients with compared with those in subjects without CDI history before enrollment (P=0.016). There were nonsignificant lower toxin A IgG levels in IBD patients with compared to without prior CDI (p=0.095) and higher levels in controls with history of prior CDI compared to IBD patients with prior CDI (p=0.049). Conclusions UC patients have lower IgA levels to C. difficile toxins compared to Crohn’s and IPAA patients. IBD patients with prior CDI failed to demonstrate any increase in anti-toxin IgG. Our findings suggest that IBD patients may benefit from immunization strategies targeting C. difficile toxins.

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“…S1 in the supplemental material). The rationale for using the acto/bezlo combination rather than bezlotoxumab alone is that the combination is required for maximal protection in rodents (14,29), despite bezlotoxumab alone being sufficient in piglets (30) and humans (16,17). At the time of C. difficile challenge, each treatment group was subdivided into two arms, a "survival" arm (n ϭ 10), in which animals were allowed to progress to the end of the study (day 28 postchallenge), and a "time point" arm (n ϭ 15), in which 5 animals were euthanized on each of days 1, 2, and 5 postchallenge, to allow direct comparison of animal results at a given time across all three treatment groups.…”

Section: Overview Of Rodent CDI Modelsmentioning

confidence: 99%

Disease Progression and Resolution in Rodent Models of Clostridium difficile Infection and Impact of Antitoxin Antibodies and Vancomycin

Warn

Thömmes

Sattar

et al. 2016

Antimicrob Agents Chemother

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bClostridium difficile causes infections of the colon in susceptible patients. Specifically, gut dysbiosis induced by treatment with broad-spectrum antibiotics facilitates germination of ingested C. difficile spores, expansion of vegetative cells, and production of symptom-causing toxins TcdA and TcdB. The current standard of care for C. difficile infections (CDI) consists of administration of antibiotics such as vancomycin that target the bacterium but also perpetuate gut dysbiosis, often leading to disease recurrence. The monoclonal antitoxin antibodies actoxumab (anti-TcdA) and bezlotoxumab (anti-TcdB) are currently in development for the prevention of recurrent CDI. In this study, the effects of vancomycin or actoxumab/bezlotoxumab treatment on progression and resolution of CDI were assessed in mice and hamsters. Rodent models of CDI are characterized by an early severe phase of symptomatic disease, associated with high rates of morbidity and mortality; high intestinal C. difficile burden; and a disrupted intestinal microbiota. This is followed in surviving animals by gradual recovery of the gut microbiota, associated with clearance of C. difficile and resolution of disease symptoms over time. Treatment with vancomycin prevents disease initially by inhibiting outgrowth of C. difficile but also delays microbiota recovery, leading to disease relapse following discontinuation of therapy. In contrast, actoxumab/bezlotoxumab treatment does not impact the C. difficile burden but rather prevents the appearance of toxin-dependent symptoms during the early severe phase of disease, effectively preventing disease until the microbiota (the body's natural defense against C. difficile) has fully recovered. These data provide insight into the mechanism of recurrence following vancomycin administration and into the mechanism of recurrence prevention observed clinically with actoxumab/bezlotoxumab. C lostridium difficile infections (CDI) are a significant cause of morbidity and mortality in the acute care setting and in the wider health care system (1-3). CDI pathogenesis is associated with use of antimicrobials that disrupt the intestinal microbiota, reducing the host's ability to resist colonization by, and expansion of, C. difficile (4, 5). These conditions allow C. difficile spores to germinate, with resultant production of two toxins, TcdA and TcdB, that cause the symptoms of the disease (6-8). The infection is normally treated with antibiotics such as vancomycin and metronidazole which have potent activity against C. difficile (1, 8). However, the broad antibacterial spectra of these agents perpetuate gut dysbiosis, leading to high rates of disease recurrence following withdrawal of therapy, during which surviving or newly acquired C. difficile spores take advantage of persistent disruption of the gut microbiome to cause another episode of CDI (9-11). The risk of recurrence following a first episode is around 25% but increases significantly with each subsequent episode, often leading to a cycle of recurrence which can ...

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Toxin-Mediated Paracellular Transport of Antitoxin Antibodies Facilitates Protection against Clostridium difficile Infection

Cited by 38 publications

References 41 publications

Immunogenicity and protective efficacy of recombinant Clostridium difficile flagellar protein FliC

Immunogenicity and protective efficacy of recombinant Clostridium difficile flagellar protein FliC

Host Immune Response to Clostridium difficile Infection in Inflammatory Bowel Disease Patients

Disease Progression and Resolution in Rodent Models of Clostridium difficile Infection and Impact of Antitoxin Antibodies and Vancomycin

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