演講時間：107年12月19日(三) 15:00~17:00

演講地點：互助大樓11A01

講者: Dr. Victor Nizet， MD.

Professor & Vice Chair for Basic Research， Department of Pediatrics Chief， Division of Host-Microbe Systems & Therapeutics University of California， San Diego School of Medicine Professor， Skaggs School of Pharmacy & Pharmaceutical Sciences Center for Immunity， Infection & Inflammation

Abstract

Group A Streptococcus (GAS) is a leading human pathogen commonly associated with pharyngitis (“strep throat”) but also capable on occasion of producing severe， invasive diseases including necrotizing fasciitis (“flesh-eating disease”) and toxic shock syndrome， even in previously healthy individuals. GAS is also the immunological trigger for rheumatic fever， a major cause of morbidity and mortality in many parts of the developing world GAS systemic disease reflects a large suite of virulence factors that enable the pathogen to avoid eradication by phagocytic defenses of the host immune system. In our studies of the globally-disseminated hyperinvasive GAS M1T1 clone， we have elucidated novel functions of four classical GAS virulence factors in modulating host immunity. The cell-wall anchored M1 protein， the most abundant and immunodominant antigen on the GAS surface， is known for its fibrinogen-binding and antiphagocytic properties. We find that the hypervariable N-terminal domain can sequester cationic cathelicidin antimicrobial peptides and histones to promote GAS resistance to killing by neutrophils and neutrophil extracellular traps. The GAS hyaluronic acid (HA) capsule is upregulated during systemic infection， and mimics a common host glycosaminoglycan to cloak opsonic targets on the bacterial surface. We reveal that GAS uses HA to engage an inhibitory Siglec receptor on the neutrophil cell surface， blunting neutrophil activation and promoting pathogen survival. The broad-spectrum GAS cysteine protease SpeB degrades host defense molecules such as antimicrobial peptides and immunoglobulins， but is paradoxically inactivated during invasive disease pathogenesis. We describe an caspase- and inflammasome-independent IL-1β signaling pathway to detect bacterial proteases that is critical in host defense against GAS. This pathway may explain an unusually high rate of severe GAS infection in patients receiving IL-1β receptor blocker therapy. Finally， we discovered the genetic basis and virulence role of the classical Lancefield group A carbohydrate antigen (GAC) that makes up 40-50% of the GAS cell wall. This knowledge allowed us to prove the role of GAC in virulence， and to developa strategy for a safe， universal GAS vaccine that eliminates a major cross-reactive antigen implicated in the pathogenesis of rheumatic heart disease.