The alternative pathway (AP) of complement (C) forms a key arm of innate immune defenses against Neisseria gonorrhoeae (Ng) infections. Properdin (P) is the only known positive regulator of C. The central theme of this proposal is to understand the role of P in Ng pathogenesis. The best known function of P is to stabilize AP C3 convertases and enhance C3 deposition. A novel mechanism of AP activation whereby P binds directly to surfaces (including Ng) and initiates AP activation has recently been described.
In Aim 1 we will measure P in cervical secretions and correlate P levels with PMN (the major reservoir for P) influx and define the role of P in activating the AP in the context of cervical secretions. Our collaborators have developed a peptide mimitope Ng vaccine directed against a conserved Ng lipooligosaccharide (LOS) structure. We will examine the role of P in AP amplification of C3 deposited by this vaccine candidate Ab. P also binds to live intact macrophages (MP) and a diverse array of apoptotic and necrotic cell lines. We hypothesize that P bound to Ng bridges bacteria to cells. We have preliminary evidence that the ligand for P on Ng is PorB.
In Aim 2 we will confirm the identity of PorB as the Ng ligand for P and define the thrombospondin type 1 repeat (TSR) domain in P (P is composed almost entirely of six TSR domains) that binds to Ng. Further, we will study the role of P in the association of Ng with MPs and viable cervical epithelial cells and cervical epithelial cells at various stages of apoptosis and necrosis. P possesses novel C-mannosyl substitutions at 14 of its tryptophan residues, making it the most heavily C-mannosylated human protein known.
In Aim 3, we will examine the role of the mannosyl residues in binding to, and activating the AP on Ng. P binds to normal (nonapoptotic) MPs and a prior study has shown that C-mannosylated TSR derived peptides bind MPs and enhance LPS-induced cytotoxicity. We hypothesize that mannose residues on P engage mannose receptors (e.g. MR and DC-SIGN) on MPs and that the P-MP interaction could decrease the TLR-4 dependant LOS signaling threshold. We will characterize the role of P mannosylaton in binding to MPs and in modulating TLR4-dependent signaling by LOS.
Gonorrhea is an important cause of morbidity worldwide. Complement is a family of proteins that forms an important arm of the natural immune defenses against Neisseria gononrhoeae. In this proposal we will define the role of properdin, an important complement activatory protein, in the pathogenesis of gonococcal infections. These studies will further our knowledge of how the immune system combats N. gonorrheae.
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