Lipolysis-stimulated lipoprotein receptor (LSR) is the host receptor for the binary toxin Clostridium difficile transferase (CDT)

Abstract

Clostridium difficile infection (CDI) causes antibiotic-associated diarrhea and pseudomembranous colitis. Hypervirulent strains of the pathogen, which are responsible for increased morbidity and mortality of CDI, produce the binary actin-ADP ribosylating toxin Clostridium difficile transferase (CDT) in addition to the Rho-glucosylating toxins A and B. CDT depolymerizes the actin cytoskeleton, increases adherence and colonization of Clostridia by induction of microtubule-based cell protrusions and, eventually, causes death of target cells. Using a haploid genetic screen, we identified the lipolysis-stimulated lipoprotein receptor as the membrane receptor for CDT uptake by target cells. Moreover, we show that Clostridium perfringens iota toxin, which is a related binary actin-ADP ribosylating toxin, enters target cells via the lipolysis-stimulated lipoprotein receptor. Identification of the toxin receptors is essential for understanding of the toxin uptake and provides a most valuable basis for antitoxin strategies.bacterial ADP-ribosyltransferases | receptor binding

GPR107, a G-protein-coupled Receptor Essential for Intoxication by Pseudomonas aeruginosa Exotoxin A, Localizes to the Golgi and Is Cleaved by Furin

“…Loss-of-function haploid genetic screens using human KBM7 cells have led to the identification of host factors essential for viral (29,50,51) and bacterial (52) pathogenesis as well as for other bacterial toxins (21,29,53). We used CRISPR/Cas9-mediated gene editing in HeLa cells to support the results obtained in the KBM7 screen.…”

Attachment ofChlamydia trachomatisL2 to host cells requires sulfation

“…We performed a loss-of-function genetic screen in human haploid cells to identify mutant cell lines resistant to Chlamydia (13)(14)(15)(16). This system avoids the potential off-target effects and incomplete knockdowns of an siRNA screen.…”

Esporas de Clostridium difficile y su relevancia en la persistencia y transmisión de la infección

“…Ambas toxinas se unen a receptores celulares promoviendo su internalización a través de endosomas, causando la alteración del citoesqueleto de actina, apoptosis, disrupción de la barrera epitelial, y una masiva respuesta inflamatoria 5 . Otro factor de virulencia presente en algunos aislados clínicos es la toxina binaria CDT (Clostridium difficile transferasa), la cual se une al receptor de lipoproteína 6 para luego ser translocada hacia el citosol y ADP-ribosilar la actina de forma irreversible promoviendo un re-ordenamiento del citoesqueleto de actina 5 . Recientemente, un estudio clínico sugiere que la toxina binaria podría estar involucrada en la recurrencia de las IACD 8 .…”