Protection from Clostridium difficile Infection in CD4 T Cell- and Polymeric Immunoglobulin Receptor-Deficient Mice

Johnston, Pehga F.; Gerding, Dale N.; Knight, Katherine L.

doi:10.1128/iai.01273-13

Cited by 33 publications

(29 citation statements)

References 41 publications

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“…2), presumably through disruption of the tight junctions that normally limit paracellular transport of molecules across the epithelium. Overall, our data preclude a role of specific Fc-dependent transport mechanisms in protection against CDI, analogous to recent data from Johnston et al (38) showing that transport of IgA via the polymeric immunoglobulin receptor (pIgR) is also not necessary for protection against CDI in mice.…”

Section: Discussionsupporting

confidence: 63%

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

et al. 2015

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bThe exotoxins TcdA and TcdB are the major virulence factors of Clostridium difficile. Circulating neutralizing antitoxin antibodies are protective in C. difficile infection (CDI), as demonstrated, in part, by the protective effects of actoxumab and bezlotoxumab, which bind to and neutralize TcdA and TcdB, respectively. The question of how systemic IgG antibodies neutralize toxins in the gut lumen remains unresolved, although it has been suggested that the Fc receptor FcRn may be involved in active antibody transport across the gut epithelium. In this study, we demonstrated that genetic ablation of FcRn and excess irrelevant human IgG have no impact on actoxumab-bezlotoxumab-mediated protection in murine and hamster models of CDI, suggesting that Fc-dependent transport of antibodies across the gut wall is not required for efficacy. Tissue distribution studies in hamsters suggest, rather, that the transport of antibodies depends on toxin-induced damage to the gut lining. In an in vitro two-dimensional culture system that mimics the architecture of the intestinal mucosal epithelium, toxins on the apical side of epithelial cell monolayers are neutralized by basolateral antibodies, and antibody transport across the cell layer is dramatically increased upon addition of toxin to the apical side. Similar data were obtained with F(ab=) 2 fragments, which lack an Fc domain, consistent with FcRn-independent paracellular, rather than transcellular, transport of antibodies. Kinetic studies show that initial damage caused by apical toxin is required for efficient neutralization by basolateral antibodies. These data may represent a general mechanism of humoral response-mediated protection against enteric pathogens.

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Section: Discussionsupporting

confidence: 63%

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

et al. 2015

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“…Mice (8 to 12 weeks old) were treated with antibiotics, including vancomycin (0.045 mg/ml), metronidazole (0.215 mg/ml), gentamicin (0.035 mg/ml), kanamycin (0.4 mg/ml), and colistin (850 U/ml), in sterile drinking water for 72 h and then were administered sterile drinking water without antibiotics for 48 h, followed by a single intraperitoneal injection of clindamycin (10 mg/kg of body weight). After 24 h, mice were challenged with 10 5 spores of epidemic C. difficile strain BI17/NAP1/027 by oral gavage (17). Mice were monitored for disease symptoms (diarrhea and weight loss) and fecal C. difficile CFU levels.…”

Section: Methodsmentioning

confidence: 99%

Analysis of Bacterial Communities during Clostridium difficile Infection in the Mouse

et al. 2015

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Clostridium difficile infection (CDI) is a major cause of health care-associated disease. CDI initiates with ingestion of C. difficile spores, germination in the gastrointestinal (GI) tract, and then colonization of the large intestine. The interactions between C. difficile cells and other bacteria and with host mucosa during CDI remain poorly understood. Here, we addressed the hypothesis that, in a mouse model of CDI, C. difficile resides in multicellular communities (biofilms) in association with host mucosa. To do this, we paraffin embedded and then sectioned the GI tracts of infected mice at various days postinfection (p.i.). We then used fluorescent in situ hybridization (FISH) with 16S rRNA probes targeting most bacteria as well as C. difficile specifically. The results revealed that C. difficile is present as a minority member of communities in the outer (loose) mucus layer, in the cecum and colon, starting at day 1 p.i. To generate FISH probes that identify bacteria within mucus-associated communities harboring C. difficile, we characterized bacterial populations in the infected mouse GI tract using 16S rRNA gene sequence analysis of bacterial DNA prepared from intestinal content. This analysis revealed the presence of genera of several families belonging to Bacteroidetes and Firmicutes. These data suggest that formation of multispecies communities associated with the mucus of the cecum and colon is an important early step in GI tract colonization. They raise the possibility that other bacterial species in these communities modulate the ability of C. difficile to successfully colonize and, thereby, cause disease.

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“…Studies in mice have also shown that mucosal IgA was induced during infection and was protective in the absence of serum IgG responses, but mucosal IgA was also dispensable since mice lacking the poly-Ig receptor had outcomes similar to those of wild-type controls (50).…”

Section: Figmentioning

confidence: 99%

Memory B Cells Encode Neutralizing Antibody Specific for Toxin B from the Clostridium difficile Strains VPI 10463 and NAP1/BI/027 but with Superior Neutralization of VPI 10463 Toxin B

et al. 2016

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T he role of immune cell memory in Clostridium difficile infection (CDI) remains poorly understood. CDI is complicated by a high frequency of recurrence, often after disease has apparently resolved, and can be associated with progressively worsening pathology and ultimately death (1). However, patients that develop antibodies (Ab) capable of neutralizing two toxins secreted by C. difficile (TcdA and TcdB) are less likely to experience recurrence (reviewed in reference 2). This suggests that memory B (Bmem) cells may contribute to resistance to reinfection by encoding toxin-neutralizing Ab. Bmem cells have typically undergone affinity maturation and Ab class switch in the germinal centers of secondary lymphoid organs (3). Bmem cells are therefore poised to respond rapidly to booster vaccinations or infection, by rapidly differentiating into plasma cells that secrete class-switched, highaffinity Ab (4). Such plasma cells may display a range of short-toextreme longevity, be associated with transient or sustained Ab titers, or secrete neutralizing or nonneutralizing Ab (5-7).In earlier studies, a correlation between bacterial load and advanced age was observed during CDI, with older individuals lacking toxin-neutralizing Ab (8). In more recent work, the probability of HIV-positive patients experiencing CDI increased as their CD4 ϩ T-cell counts declined (9), which could be partly attributable to altered CD4 ϩ T-cell-dependent B cell function (10). Indeed, there is growing concern about CDI in a variety of immunocompromised individuals, including organ transplant recipients (reviewed in reference 11). These observations highlight the wellrecognized importance of B cell responses and production of toxin-neutralizing antibodies in resisting CDI. However, the underlying characteristics of the Bmem cellular response and their contributions to production of toxin-neutralizing Ab have not been described.CDI is best known as a disease of the gastrointestinal tract, causing diarrhea, and this infection may progress to a severe pathological condition in which pseudomembranous colitis and toxic megacolon are evident (1, 2). However, CDI-associated mortality may be attributable to systemic sequelae of the disease (12). Although large-scale epidemiological studies are lacking, reported systemic complications include hepatic abscesses (13), ascites (14), pleural effusion with acute respiratory distress (15, 16), and severe sepsis and multiorgan dysfunction (17).TcdA and TcdB are large clostridial toxins that contribute sub-

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Protection from Clostridium difficile Infection in CD4 T Cell- and Polymeric Immunoglobulin Receptor-Deficient Mice

Cited by 33 publications

References 41 publications

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

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

Analysis of Bacterial Communities during Clostridium difficile Infection in the Mouse

Memory B Cells Encode Neutralizing Antibody Specific for Toxin B from the Clostridium difficile Strains VPI 10463 and NAP1/BI/027 but with Superior Neutralization of VPI 10463 Toxin B

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