Inorganic polyphosphate in host and microbe biology

Abstract

Inorganic polyphosphate (polyP) is produced by both bacteria and their eukaryotic hosts, and it appears to play multiple important roles in the interactions between those organisms. However, the detailed mechanisms of how polyP synthesis is regulated in bacteria, and how it influences both bacterial and host biology, remain largely unexplored. In this review, we examine recent developments in the understanding of how bacteria regulate the synthesis of polyP, what roles polyP plays in controlling virulence in pathogenic bacteria, and the effects of polyP on the mammalian immune system, as well as progress on developing drugs that may be able to target bacterial polyP synthesis as novel means of treating infectious disease.

Keywords: bacterial survival; immune regulation; pathogenicity; polyphosphate.

Figure 1.. The structure and regulation of polyP in bacteria.

(A) The structure of polyP. A short polyP molecule (polyP₁₀). Bacterial polyP can be up to 1000 phosphate units long, while eukaryotic polyP is usually substantially shorter. (B) The current model for polyP regulation in Escherichia coli. PolyP is synthesized by polyP kinase (PPK) and degraded by exo-polyPase (PPX). Starvation stress stimulates RelA and SpoT to synthesize (p)ppGpp, which inhibits PPX, but does not influence PPK activity and is not required for induction of polyP synthesis. Induction of polyP synthesis does depend on the transcription factors RpoN, RpoE, DksA, and PhoB, although none of these activate transcription of the ppk gene itself. PhoU is a negative regulator of both phosphate transport and polyP synthesis. None of the mechanism(s) by which these regulators affect PPK activity are currently known.

Figure 2.. The PolyP Wars: The Struggle Between Host and Pathogen PolyP.

A) Host polyP utilization begins as soon as damage is detected, with platelets releasing short-chain polyP (scPolyP) to accelerate thrombin-dependent clotting and neutrophil recruitment. Host polyP also drives macrophage differentiation into the pro-inflammatory M1 phenotype that facilitates rapid phagocytosis and clearance of pathogens. B) Meanwhile, pathogenic bacteria utilize long-chain polyP (lcPolyP) to impair the host immune response, driving the anti-inflammatory M2 activation of macrophages while also impairing the expression of MHC Class II molecules to hamper the adaptive immune response. C) Internally, bacteria utilize lcPolyP for a wide variety of functions from stabilizing damaged proteins to regulating expression of crucial stress response and virulence factors. The two sides clash in an age-old contest using an ancient biomolecule as their weapon of choice. Figure created using BioRender.