Title : The mechanisms of innate immune responses in streptococcus pyogenes pathogenicity

Abstract:

A signature feature of Group A Streptococcus pyogenes (GAS) infections in humans is dysregulated hemostasis.  Hemostasis is a component of the innate immune system, which also includes inflammation and complement activation, all of which attempt to eliminate the invading bacteria.  An initial response to GAS infection of the host is to activate the coagulation and inflammatory systems to entrap and eliminate the invading bacteria within a fibrin clot.  The bacteria respond by conscription of the host protein, plasminogen, which is activated by the GAS-secreted plasminogen activator, streptokinase, to a potent protease, plasmin, which resides on the bacterial surface. 

Cell bound plasmin resolves the clot and liberates the bacteria to disseminate to deep tissue sites via its cell surface proteolytic activity.  The clot is also an inflammatory mediator acting through attraction of leukocytes and induction of cytokines and chemokines. Additionally, during the process of clot formation, proteases are released that further stimulate the inflammatory system through cellular protease receptors.  As a further component of the host defense system, the vasoactive and potent inflammatory peptide, bradykinin, is also formed, further stimulating inflammation and complement activation, again in an attempt to eliminate the microorganism.  The inflammatory mediators then crosstalk with hemostasis system components to further upregulate thrombosis, thus continuing this vicious cycle of coagulation-inflammation. 

The complex interplay of these systems can lead to dire consequences for the host when hemostasis-inflammation is dysregulated by bacterial and host responses.  In this discussion, we will assess the biological mechanisms that must be controlled in the tug of war for survival between GAS and the human host. A comprehensive understanding of the mechanisms associated with GAS virulence and the host response to these infections could lead to novel approaches for altering the course of GAS infectivity.

Biography:

Professor Francis J. Castellino obtained his B.S in Chemistry from the University of Scranton, his M.S. and Ph.D. degrees in Biochemistry from the University of Iowa and was a postdoctoral fellow at Duke University. He currently is the Kleiderer/Pezold Professor of Biochemistry and Director of the WM Keck Center for Transgene Research, University of Notre Dame.  The research interests of Prof. Castellino’s laboratory involve the in vitro, in vivo, and ex vivo structure, function, and activation of components of blood coagulation and blood clot dissolution and their relationships to inflammatory and infectious disease.  He, as an author and co-author of more than 500 articles in scholarly journals, which have around 21,000 citations.