Molecular Mimicry of Host Sialome by Human Pathogens to exploit Immunoregulatory Siglecs

Abstract

This thesis focuses on the characterization of two human-specific pathogens that mimic host sialic acid surface structures to engage human immunoregulatory Siglec receptors. Furthermore, it explores the use of sialic acid and sialic acid-like molecules as tools and therapeutics. The first chapter introduces the different types of sialic acids and their diverse functions in prokaryotes and eukaryotes. It reviews different viral, bacterial, fungal and parasitic pathogens that use sialic acid, in particular as molecular mimicry, to engage the host and subvert the host immune system. The second chapter characterizes the interactions between Escherichia coli K1, which mimics host polysialic acid, and the paired receptors Siglec-11 and Siglec-16. E. coli K1 engages the inhibiting receptor Siglec-11 to escapes killing. In contrast, binding to Siglec-16, an activating immunoregulatory receptor, increases inflammatory responses and phagocytosis. Chapter two also introduces a murine model to study the interaction of pathogens with paired receptors. The third chapter describes interactions between Neisseria gonorrhoeae, the causative agent of gonorrhea, and human Siglecs as well as their potential impact on pathogenesis. The interactions are mediated by sialylated lipooligosaccharide (LOS) structures that mimic human glycosphingolipids. Additionally, gonococcal porins engage Siglecs in a sialic acid-independent manner. In many individuals, a fusion event between SIGLEC5 and SIGLEC14 genes and a polymorphism in the SIGLEC16 allele lead to the loss of functional Siglec-14 and Siglec-16, respectively. The impact of the loss of these activating receptors on the infection rate is explored in a remote population of Namibian pastoralists, which have a high burden of gonorrhea. The increasing number of infections and antibiotic resistance of N. gonorrhoeae pose a risk to the future of gonorrhea treatment. Chapter 3 introduces a novel therapeutic strategy to that may treat and prevent gonococcal infections. N. gonorrhoeae incorporates host sialic acid into its LOS to inhibit the classical and alternative pathway of the host complement system. N. gonorrhoeae also incorporates sialic acid analogs (e.g. legionaminic acid) into its LOS, which are usually not available to the pathogen. Consequently, it is not able to inhibit the classical pathway anymore. Administration of legionaminic acid to a gonorrhea mouse model leads to a reduced clearance time and infection burden. The 9-O-acetyl modification of sialic acid is very common in humans and other animals. However, it is very difficult to study since this modification is very unstable. The addendum chapter suggests a chemical solution to this problem. The oxygen atom in the 9-O-acetyl group is substituted by a nitrogen atom, which leads to a chemically and biologically stable 9-N-acetyl group. This simple approach opens up many new opportunities to study 9-O-acetylated sialic acid, for example its role in host-pathogen interactions.