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Polyphosphate as a modulator of the complement system Wat, Jovian Ming Wai

Abstract

Coagulation and complement are evolutionarily related, with several well-described mechanisms of cross-talk. Recently, it was established that polyphosphate (polyP) is a physiologic activator and promoter of coagulation. I hypothesized that polyP also plays a role in regulating complement, and thereby acts as an additional molecular bridge between coagulation and complement. Evidence to support this was provided by studies in bacteria, where defects in polyP synthesis and degradation alter its resistance to serum-mediated killing. In this thesis, I show that polyP suppresses total complement-mediated lytic activity and the terminal pathway, resulting in decreased lysis of foreign erythrocytes by the membrane attack complex (MAC). In contrast, monophosphate exhibits 10-fold less inhibition in total hemolytic activity, and has no effect on the terminal pathway. I also provide evidence that polyP destabilizes the C5b,6 complex to prevent functional MAC formation. Implications of the role of polyP in complement modulation are discussed.

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Attribution-NonCommercial-NoDerivatives 4.0 International

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