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WCID 2025

Binding and activation of fibrinolytic components to group A streptococcus pyogenes enhances microbial pathogenicity

Francis J Castellino, Speaker at Infection Conferences
University of Notre Dame, United States
Title : Binding and activation of fibrinolytic components to group A streptococcus pyogenes enhances microbial pathogenicity

Abstract:

Binding and activation of components of the human fibrinolytic system enhances the pathogenicity of Streptococcus pyogenes (GAS) by allowing a potent serine protease, human plasmin (hPm) to be present on the surface of these cells. The major receptors of hPg and hPm on these cells are streptococcal M-protein (PAM) of Pattern D strains of GAS, as well as streptococcal enolase (SEn). We have studied the binding of intact hPg to these proteins at high resolution using cryogenic electron microscopy (cryoEM) and have obtained resolutions <3.6Å, thus allowing the mechanisms of binding to be determined. These studies were combined with activation analyses of hPg by GAS-secreted streptokinase (SK) to correlate plasminogen binding, activation and pathogenicity. We find that only Pattern D strains of GAS directly bind hPg and hPm via a short region of the hPg, termed kringle 2, and the a-domain of PAM. Binding to SEn is more complex with several hPg kringles interaction with an internal lysine isostere of SEn. However, the complex of Sen and hPg does not result in its enhanced activation by SK, but this binding does promote slightly enhanced activation of hPg by host tissue-type plasminogen activator. We conclude that the pathogenicity of Pattern D GAS is primarily accomplished by hPg binding to PAM.

Biography:

Dr. Castellino studied Chemistry as an undergraduate at the University of Scranton (PA) and graduated with a BS in 1964. He then was a graduate student in Biochemistry at the University of Iowa with Robert Barker, where he graduated with a M.S. and PhD. In 1968. Following this, he was a postdoctoral fellow at Duke University with Robert L Hill. Dr. Castellino joined the Department of Chemistry and Biochemistry at the University of Notre Dame in 1970, where he remained to this day. He is currently the Kleiderer-Pezold Professor of Biochemistry.

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