TheThe Streptococcus pneumoniae IgA1 Protease: from molecular mechanism to vaccine development.
EMSL Project ID
50714
Abstract
Streptococcus pneumoniae remains a “major global public health problem” according to the World Health Organization with an alarming increase in non-vaccine serotypes, prompting the immediate need to develop universal vaccines against SPN virulence factors and identify therapeutic targets to block infection. The SPN IgA1 Protease (IgA1P) is proposed to be an ideal target, as it is a widely conserved virulence factor that suppresses the host response by cleaving host IgA1 at its hinge region. Our goals here are to address the underlying mechanism of this unique IgA1P virulence factor that shares virtually no sequence homology with any other known protein other than a conserved zinc binding motif that we have recently shown defines this enzyme as a metalloproteinase. We will specifically determine the structure of the IgA1P alone (Aim 1), determine its structure with a first generation neutralizing monoclonal antibody that we have developed (Aim 2), and determine the structure of an inactive mutant that we have shown still binds its IgA1 substrate (Aim 3). The potential global impact of these studies is to utilize structure-based initiatives to identify surface exposed immunogenic regions that may serve as vaccines against the SPN IgA1P. More broadly, these proposed studies provide a powerful platform for identifying immunogenic sites of SPN surface exposed virulence factors through rational structural approaches and create a pipeline for vaccine production through our continued collaboration with Mucosal and Vaccine Research Colorado program.
Project Details
Start Date
2019-03-15
End Date
2020-02-14
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members