Abstract
This PhD project aims to investigate the virulent roles of IgA1 proteases during infections with pathogenic Neisseria species. Immunoglobulin A1 (IgA1) is a major antibody class that provides the first line of defense on mucosal surfaces. However, some pathogenic bacteria such as Neisseria gonorrhoeae and Neisseria meningitidis secrete IgA1 proteases to evade the immune response, and their specific impact on bacterial virulence remains unclear. Therefore, this PhD project aims to investigate the effect of neisserial IgA1 proteases on virulence. Specifically, we will develop a set of reagents for highly sensitive and selective detection of IgA1 proteases. To achieve the desired outcomes, this PhD project is outlined in three specific aims: (I) synthesizing highly sensitive peptide substrates as potential diagnostic tools, (II) developing activity-based chemical probes for in vivo monitoring of protease activity, and (III) exploring cyclic peptides containing a diphenyl phosphonate warhead as irreversible inhibitors. The successful execution of the project will provide valuable insights into the pathogenesis of neisserial infections and contribute to the development of novel anti-infective drugs and diagnostic tools. Given the emergence of high-level resistance strains of N. gonorrhoeae and the lack of rapid diagnostic tests for N. meningitidis, the project's outcomes can be a great asset to biomedical research on IgA1 proteases.
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