Bacterial polyphosphates interfere with the innate host defense to infection

Abstract

Polyphosphates are linear polymers and ubiquitous metabolites. Bacterial polyphosphates are long chains of hundreds of phosphate units. Here, we report that mouse survival of peritoneal Escherichia coli sepsis is compromised by long-chain polyphosphates, and improves with bacterial polyphosphatekinase deficiency or neutralization using recombinant exopolyphosphatase. Polyphosphate activities are chain-length dependent, impair pathogen clearance, antagonize phagocyte recruitment, diminish phagocytosis and decrease production of iNOS and cytokines. Macrophages bind and internalize polyphosphates, in which their effects are independent of P2Y1 and RAGE receptors. The M1 polarization driven by E. coli derived LPS is misdirected by polyphosphates in favor of an M2 resembling phenotype. Long-chain polyphosphates modulate the expression of more than 1800 LPS/TLR4-regulated genes in macrophages. This interference includes suppression of hundreds of type I interferonregulated genes due to lower interferon production and responsiveness, blunted STAT1 phosphorylation and reduced MHCII expression. In conclusion, prokaryotic polyphosphates disturb multiple macrophage functions for evading host immunity.

Inorganic polyphosphate modulates leukocyte accumulation and vascular endothelial cell permeability and ameliorates cecal ligation and puncture-induced lethality

“…It has already been demonstrated that polyP shows biological effects in a chain length-dependent manner (Angelova et al, 2016). Indeed, bacterial long-chain polyP has been shown to potentiate pathogenicity by inhibiting phagosome maturation (Roewe et al, 2020) and interfering with macrophage function (Rijal et al, 2020). Therefore, it is suggested that the response of polyP to inflammation will be different depending on the dose and degree of polymerization.…”

Nanomedicine: A Diagnostic and Therapeutic Approach to COVID-19

“…Early and rapid detection is key for lowering the basic reproduction number of infected individuals. Nanoparticles can be engineered as biosensors for the detection of biomarkers, including nucleic acids (DNA, RNA), specific antigens (proteins, enzymes), or antibodies in order to rapidly and accurately detect SARS-CoV-2 (143,149,181,182). Recent advancements in nanotechnology have allowed for the release of a SARS-CoV-2 detection platform that uses graphene conjugated to an anti-spike antibody.…”

The promises of lysine polyphosphorylation as a regulatory modification in mammals are tempered by conceptual and technical challenges

“…Manipulation of polyP levels has been proposed as a therapeutic for ulcerative colitis, [ 75 ] bacterial [ 64 ] and viral infection, [ 68,76 ] and wound healing. [ 77 ] Given the breadth of processes impacted by polyP, we are likely to see additional clinical applications in the near future.…”

“…Finally, recent work by Roewe et al presents data suggesting that macrophages can internalize bacterial long-chain polyP and that this inhibits the immune response. [64] Here again, it would be interesting to test if this results in polyphosphorylation of mammalian proteins involved in infection control. It is also tempting to speculate that such polyphosphorylations might be prevented by treatment with mesalamine, a drug used to treat inflammatory bowel disease that serves as an inhibitor of bacterial PPK enzymes.…”