# Bacterial polyphosphates in sepsis

> **NIH NIH R01** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2021 · $537,125

## Abstract

Project Summary: Sepsis remains a leading cause of morbidity and mortality with almost 50 million cases per
year worldwide. In the absence of FDA-approved drugs, there is a high demand for better insights into the host-
microbe interactions that define the molecular pathogenesis of sepsis. Polyphosphates are linear polymers of
inorganic phosphate (Pi) residues that are present in all living organisms. The metabolism of bacteria
accumulates long-chains of polyphosphates (Pi: n≥1,000) in contrast to the short-chain polyphosphates (Pi:
n<100) typically found in mammalian cells. The biologic effects are dependent on chain length. Emerging data
suggest that short-chain polyphosphates modulate blood coagulation and inflammation, while the role of long-
chain, bacteria-derived, polyphosphates in sepsis is an understudied research field. Our preliminary work
suggests that neutralization of polyphosphates or bacterial polyphosphate deficiency improves survival of
peritoneal sepsis induced by cecum ligation and puncture (CLP) in mice. In sterile macrophage cultures, long-
chain polyphosphates modulate LPS/TLR4-induced macrophage polarization, iNOS expression and immuno-
metabolism. Here, we propose to test the central hypothesis that bacterial polyphosphates are lethal metabolites
in sepsis because of their detrimental interference with the innate host response to infection. To shed light into
the biological activities of polyphosphates, we propose to address 3 specific aims: (1) To study the effects of
polyphosphate neutralization, we will use a recombinant exopolyphosphatase (PPX) protein and characterize its
activities on the host response to polymicrobial CLP sepsis. A single-cell proteogenomics approach (CITE-Seq)
will aim to capture the heterogeneity/polarization of invading professional phagocytes as a function of
polyphosphates. The polyphosphates will be measured in sepsis samples of mice and humans. (2) To
characterize the direct interference of polyphosphates with the functions of cultured macrophages, we will
combine bacterial TLR agonists with synthetic polyphosphates of different chain length. It will be studied if
polyphosphates curb STAT/IRF signaling pathways for modulating iNOS, L-arginase, cytokines/chemokines,
and metabolic reprogramming (OXPHOS, glycolysis). In addition, affinity purification combined with label-free
proteomics will aim for the identification of novel polyphosphate targeted proteins in macrophages; to better
understand the mechanisms how polyphosphates interfere with phagocyte responses in sepsis. (3) In gnotobiotic
mice, monocolonized with a polyphosphate-deficient E. coli mutant (Δppk), we will investigate how bacteria-
derived polyphosphates shape innate immunity before and after monomicrobial CLP sepsis. Peritoneal and
intestinal mucosal macrophages will be characterized and compared for their functions, transcriptome plasticity
and immuno-metabolic phenotypes. This research project will provide novel insights into...

## Key facts

- **NIH application ID:** 10210680
- **Project number:** 1R01AI153613-01A1
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Markus Bosmann
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $537,125
- **Award type:** 1
- **Project period:** 2021-02-22 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10210680

## Citation

> US National Institutes of Health, RePORTER application 10210680, Bacterial polyphosphates in sepsis (1R01AI153613-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10210680. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*