Human Serum Albumin Is an Essential Component of the Host Defense Mechanism Against Clostridium difficile Intoxication

Masi, Alessandra di; Leboffe, Loris; Polticelli, Fabio; Tonon, Federica; Zennaro, Cristina; Caterino, Marianna; Stano, Pasquale; Fischer, Stephan; Hägele, Marlen; Müller, Martin C.; Kleger, Alexander; Papatheodorou, Panagiotis; Nocca, Giuseppina; Arcovito, Alessandro; Gori, Andrea; Ruoppolo, Margherita; Barth, Holger; Petrosillo, Nicola; Ascenzi, Paolo; Bella, Stefano Di

doi:10.1093/infdis/jiy338

Cited by 51 publications

(52 citation statements)

References 38 publications

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“…Human miniguts are derived from plucked hair form a healthy donor and contain crucial characteristics of human guts . For the transmembrane adhesion protein E‐Cadherin as well as for F‐actin, clear cytotoxic effects caused by bacterial toxins were reported . We observed that α‐defensin‐1 was able to protect the organoids from intoxication with the medically relevant combination of TcdA, TcdB, and CDT and prevented the tissue damage caused by the bacterial toxins.…”

Section: Discussionmentioning

confidence: 81%

Human peptide α‐defensin‐1 interferes withClostridioides difficiletoxins TcdA, TcdB, and CDT

et al. 2020

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The human pathogenic bacterium Clostridioides difficile produces two exotoxins TcdA and TcdB, which inactivate Rho GTPases thereby causing C. difficile‐associated diseases (CDAD) including life‐threatening pseudomembranous colitis. Hypervirulent strains produce additionally the binary actin ADP‐ribosylating toxin CDT. These strains are hallmarked by more severe forms of CDAD and increased frequency and severity. Once in the cytosol, the toxins act as enzymes resulting in the typical clinical symptoms. Therefore, targeting and inactivation of the released toxins are of peculiar interest. Prompted by earlier findings that human α‐defensin‐1 neutralizes TcdB, we investigated the effects of the defensin on all three C. difficile toxins. Inhibition of TcdA, TcdB, and CDT was demonstrated by analyzing toxin‐induced changes in cell morphology, substrate modification, and decrease in transepithelial electrical resistance. Application of α‐defensin‐1 protected cells and human intestinal organoids from the cytotoxic effects of TcdA, TcdB, CDT, and their combination which is attributed to a direct interaction between the toxins and α‐defensin‐1. In mice, the application of α‐defensin‐1 reduced the TcdA‐induced damage of intestinal loops in vivo. In conclusion, human α‐defensin‐1 is a specific and potent inhibitor of the C. difficile toxins and a promising agent to develop novel therapeutic options against C. difficile infections.

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Section: Discussionmentioning

confidence: 81%

Human peptide α‐defensin‐1 interferes withClostridioides difficiletoxins TcdA, TcdB, and CDT

et al. 2020

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“…hypothesized that human serum albumin (HSA) could have a neutralizing effect on clostridial toxins. 117 TcdA and TcdB induced epithelial damage, particularly in the crypt-like regions of HIOs; however, HIOs incubated with toxins and HSA had reduced pathology. While the mechanism is not completely understood, the authors speculate that HSA might bind to the toxins in the bloodstream and induce conformational changes, leading to toxin autoproteolysis.…”

Section: Introductionmentioning

confidence: 89%

Research in a time of enteroids and organoids: how the human gut model has transformed the study of enteric bacterial pathogens

et al. 2020

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Enteric bacterial pathogens cause significant morbidity and mortality globally. Studies in tissue culture and animal models shaped our initial understanding of these host-pathogen interactions. However, intrinsic shortcomings in these models limit their application, especially in translational applications like drug screening and vaccine development. Human intestinal enteroid and organoid models overcome some limitations of existing models and advance the study of enteric pathogens. In this review, we detail the use of human enteroids and organoids to investigate the pathogenesis of invasive bacteria Shigella, Listeria, and Salmonella, and noninvasive bacteria pathogenic Escherichia coli, Clostridium difficile, and Vibrio cholerae. We highlight how these studies confirm previously identified mechanisms and, importantly, reveal novel ones. We also discuss the challenges for model advancement, including platform engineering to integrate environmental conditions, innate immune cells and the resident microbiome, and the potential for pre-clinical testing of recently developed antimicrobial drugs and vaccines.

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“…The GA module was shown to interact with a hydrophobic pocket formed by Met‐329, Phe‐309, and Phe‐326 located in Domain II of albumin . On the other hand, docking analyses conducted by di Masi et al predicted that domain II of HSA interacts with hydrophobic portions of the DD domain of Clostridium difficile toxins …”

Section: Discussionmentioning

confidence: 99%

“…36 On the other hand, docking analyses conducted by di Masi et al predicted that domain II of HSA interacts with hydrophobic portions of the DD domain of Clostridium difficile toxins. 37 Subsequently, we have successfully produced a recombinant HSA mutant Domain II with increased binding capacity to Aβ, using a phage display approach. It is expected that this HSA mutant domain will be a competent chaperone for peripheral interventions and is expected to have the least possibility of triggering immune responses.…”

Section: Discussionmentioning

confidence: 99%

Albumin domain mutants with enhanced Aβ binding capacity identified by phage display analysis for application in various peripheral Aβ elimination approaches of Alzheimer's disease treatment

et al. 2019

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Deposition of amyloid protein, particularly Aβ1‐42, is a major contributor to the onset of Alzheimer's disease (AD). However, almost no deposition of Aβ in the peripheral tissues could be found. Human serum albumin (HSA), the most abundant protein in the blood, has been reported to inhibit amyloid formation through binding Aβ, which is believed to play an important role in the peripheral clearance of Aβ. We identified the Aβ binding site on HSA and developed HSA mutants with high binding capacities for Aβ using a phage display method. HSA fragment 187–385 (Domain II) was found to exhibit the highest binding capacity for Aβ compared with the other two HSA fragments. To elucidate the sequence that forms the binding site for Aβ on Domain II, a random screening of Domain II display phage biopanning was constructed. A number of mutants with higher Aβ binding capacities than the wild type were identified. These mutants exhibited stronger scavenging abilities than the wild type, as revealed via in vitro equilibrium dialysis of Aβ experiments. These findings provide useful basic data for developing a safer alternative therapy than Aβ vaccines and for application in plasma exchange as well as extracorporeal dialysis.

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Human Serum Albumin Is an Essential Component of the Host Defense Mechanism Against Clostridium difficile Intoxication

Abstract: Our data provide evidence for a specific HSA-dependent self-defense mechanism against C difficile toxins and provide an explanation for the clinical correlation between CDI severity and hypoalbuminemia.

Cited by 51 publications

References 38 publications

Human peptide α‐defensin‐1 interferes withClostridioides difficiletoxins TcdA, TcdB, and CDT

Human peptide α‐defensin‐1 interferes withClostridioides difficiletoxins TcdA, TcdB, and CDT

Research in a time of enteroids and organoids: how the human gut model has transformed the study of enteric bacterial pathogens

Albumin domain mutants with enhanced Aβ binding capacity identified by phage display analysis for application in various peripheral Aβ elimination approaches of Alzheimer's disease treatment

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