Activation of the inflammasome by bacterial protein toxins targeting the cytoskeleton

• Autores: Rincón, María Gabriela
• Año de publicación: 2019
• Idioma: inglés
• Tipo de recurso: tesis de maestría
• Colaborador/a o director/a de tesis: Radice, Marcela; Aktories, Klaus; Cerquetti, Cristina; Hozbor, Daniela; Borner, Christoph
• Materia: Inflamasomainducida; Inflammasome; Clostridium difficile; Cytoskeleton; Ciencias de la vida
• Institución: Universidad de Buenos Aires

The inflammasome is a complex present in the cytosol of stimulated immune cells that leads\nto the activation of pro-inflammatory caspase-1. Active caspase-1 is responsible for the release\nof the pro-inflammatory interleukin-1? (IL-1?) and IL-18, and cleavage of Gasdermin-D, which\nultimately results in a form of lytic cell death known as pyroptosis. Clostridium difficile is an\nanaerobe, spore-forming bacterium that can cause antibiotic-related diarrhea and\npseudomembranous colitis. Major virulence factors of this pathogen are the Rho-glycosylating\ntoxins A and B (TcdA, TcdB), which inactivate Rho-GTPases. Hyper virulent strains of\nClostridium difficile also produce the binary toxin C. difficile transferase (CDT). CDT ADPribosylates\nmonomeric G-actin resulting in complete depolymerization of the actin\ncytoskeleton. Previously, first studies about the influence of TcdA and TcdB onr inflammasome\nactivation have been reported. Morer recently, it was identified that Pyrin, a protein capable of\nassembling the inflammasome, acts as a sensor responsible for detecting the inactivation of\nRho GTPases. Since no direct binding of the modified GTPases to Pyrin was observed, the\nauthors concluded that Pyrin likely senses the effects of GTPase inactivation on the actin\ncytoskeleton. Interactions of Pyrin and other ?receptors? activating the inflammasome with\ncomponents of the cytoskeleton indicate that alteration of cytoskeletal dynamics plays an\nimportant role in inflammasome activation. Considering this, we decided to evaluate if CDT\ncould activate the inflammasome, and to further characterize inflammasome activation by\nTcdB. Our results show that both TcdB and CDT are capable of inducing ASC speck formation\nand release of IL-1? from competent immune cells. TcdB also induced activation of caspase-\n1 and pyroptosis, and we found evidence that TcdB influences several receptors involved in\ninflammasome assembly. This data confirm the important role of clostridial toxins that target\nthe cytoskeleton in exerting inflammatory responses in the host.
Fil: Rincón, María Gabriela. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Buenos Aires, Argentina
Magíster de la Universidad de Buenos Aires en Ciencias Biomédicas