Human Defensins Facilitate Local Unfolding of Thermodynamically Unstable Regions of Bacterial Protein Toxins

Kudryashova, Elena; Quintyn, Royston S.; Seveau, Stéphanie; Lu, Wuyuan; Wysocki, Vicki H.; Kudryashov, Dmitri S.

doi:10.1016/j.immuni.2014.10.018

Cited by 74 publications

(95 citation statements)

References 57 publications

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“…Another reason may be that other IgG-independent mechanisms could contribute to protection, and this could also explain why the in vitro neutralization assay was better able to discriminate between experimental groups than the in vivo challenge assay. Indeed, ␣-defensins were recently shown to contribute to neutralization of TcdB1 in a manner dependent on binding to the N terminus of the protein, thus suggesting that neutralization could be complementary to that provided by C terminus-targeting IgG (51,52).…”

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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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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“…Moreover, defensins can also affect the microbial intracellular processes, such as inhibiting protein synthesis [65] and the activities of ␣-amylases [60] and proteases [106]. Alternatively, these peptides can also induce the inactivation of microbial toxins by protein unfolding [48].…”

Section: Introductionmentioning

confidence: 99%

Cysteine-stabilized αβ defensins: From a common fold to antibacterial activity

Dias

Franco

2015

Peptides

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Antimicrobial peptides (AMPs) seem to be promising alternatives to common antibiotics, which are facing increasing bacterial resistance. Among them are the cysteine-stabilized αβ defensins. These peptides are small, with a length ranging from 34 to 54 amino acid residues, cysteine-rich and extremely stable, normally composed of an α-helix and three β-strands stabilized by three or four disulfide bonds and commonly found in several organisms. Moreover, animal and plant CSαβ defensins present different specificities, the first being mainly active against bacteria and the second against fungi. The role of the CSαβ-motif remains unknown, but a common antibacterial mechanism of action, based on the inhibition of the cell-wall formation, has already been observed in some fungal and invertebrate defensins. In this context, the present work aims to group the data about CSαβ defensins, highlighting their evolution, conservation, structural characteristics, antibacterial activity and biotechnological perspectives.

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“…The AMPs secreted by Paneth cells include cryptdin, Reg3γ, lysozyme and so on (Bevins and Salzman, 2011;Clevers and Bevins, 2013). Cryptdin suppresses pathogenic microbes and neutralizes a range of bacterial toxins (Kudryashova et al, 2014). Reg3γ specifically kills Gram-positive bacteria, suggesting that each AMP has its own antimicrobial spectrum.…”

Section: Reciprocal Interaction Between Paneth Cells and Microbesmentioning

confidence: 99%

Paneth cells: the hub for sensing and regulating intestinal flora

Zhang

Liu

2016

Sci. China Life Sci.

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The complex interplay between symbiotic bacteria and host immunity plays a key role in shaping intestinal homeostasis and maintaining host health. Paneth cells, as one of the major producers of antimicrobial peptides in the intestine under steady-state conditions, play a vital role in regulating intestinal flora. Many studies on inflammatory bowel disease (IBD)-associated genes have put Paneth cells at the center of IBD pathogenesis. In this perspective, we focus on mechanistic studies of different cellular processes in Paneth cells that are regulated by various IBD-associated susceptibility genes, and we discuss the hypothesis that Paneth cells function as the central hub for sensing and regulating intestinal flora in the maintenance of intestinal homeostasis. inflammatory bowel disease, Paneth cell, commensal bacteria, intestinal homeostasisCitation:

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Human Defensins Facilitate Local Unfolding of Thermodynamically Unstable Regions of Bacterial Protein Toxins

Cited by 74 publications

References 57 publications

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

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

Cysteine-stabilized αβ defensins: From a common fold to antibacterial activity

Paneth cells: the hub for sensing and regulating intestinal flora

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