Endothelial inflammasome activation induced by group A streptococcus

Abstract

The most severe form of invasive GAS disease is necrotizing fasciitis described as rapidly muscle destruction with marked coagulation disturbance and vascular dysfunction In response to invasive GAS disease a large quantity of proinflammatory cytokine IL-1? is induced and associated with vascular dysfunction disseminated intravascular coagulation (DIC) microvascular leakage and multiple organ dysfunctions IL-1β is known to be processed by caspase-1 a cysteine protease regulated by a multiprotein complex called inflammasome However the pathogenesis in necrotizing fasciitis is so complicated that many fundamental questions remain poorly understood Here we successfully reconstructed the animal model of necrotizing fasciitis that myonecrosis and vascular damages were induced by intramuscular injection of GAS and inflammasome activation accompanied with large amount of IL-1β production were found In addition endothelial inflammasome activations were induced by GAS infection Pyroptosis markers released LDH and HMGB-1 and extracellular bacterial numbers were prohibited by caspase-1 inhibitor in GAS-infected endothelial cells Blockage of caspase-1 in vivo prevented GAS-induced muscular inflammasome activation and muscular damage Further we demonstrated that streptolysin S of GAS involved in GAS-induced endothelial inflammasome activation and pyropotosis by infection with isogenic SLS mutant In addition the SLS mutant lost its capacity causing muscular inflammasome activation and severe muscle destruction in vivo Taken together we demonstrated that phagosomal escaped GAS which mediated by SLS induced severe muscle destruction was mediated through endothelial inflammasome activation accompanied with a canonical caspase-1 dependent pyroptosis and further released the cytosomal GAS Thus we hypothesized that rapid muscle destruction induced by GAS is the consequence of excessive inflammatory responses followed by endothelial inflammasome activation

Date of Award	2014 Feb 13
Original language	English
Supervisor	Pei-Jane Tsai (Supervisor)