Research Pooja Thomas

Abstract

Immunoglobulin A1 (IgA1) is the predominant antibody on mucosal surfaces and provides a critical first line of defense. Pathogenic Neisseria species, including N. meningitidis (NM) and N. gonorrhoeae (NG), evade this defense by secreting IgA1 proteases (IgA1Ps) that target IgA1. Although IgA1Ps are exclusively produced by pathogenic Neisseria, their precise contributions to virulence remain unclear. Understanding how these proteases contribute to Neisseria virulence is crucial, particularly given the rise of antibiotic-resistant NG strains and the need for rapid diagnostics for invasive NM infections. This project aims to comprehensively characterize IgA1Ps in Neisseria infections. We will first map IgA1P substrate specificity beyond IgA1, identifying novel host targets using N-terminomics and combinatorial peptide libraries. Based on these insights, we will develop and optimize activity-based probes (ABPs) to selectively detect and track IgA1P activity. These probes will allow direct monitoring of IgA1P activity during infection using confocal microscopy, providing unprecedented insights into when and where IgA1Ps are active in human epithelial, endothelial, and neuronal cell models. By unraveling IgA1P's role in pathogenesis, we aim to identify new avenues for anti-infective therapies and early detection strategies.

Researcher(s)

• Promoter: Prothiwa Michaela
• Fellow: Thomas Pooja

Research team(s)

• Medicinal Chemistry (UAMC)

Project type(s)

• Research Project

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.

Researcher(s)

• Promoter: Prothiwa Michaela
• Fellow: Thomas Pooja

Research team(s)

• Medicinal Chemistry (UAMC)

Project type(s)

• Research Project