Polyphosphates as Novel Pathogen-Associated Molecular Patterns in Macrophages

• Applicant: Professor Dr. Markus Bosmann
• Subject Area: Pneumology, Thoracic Surgery
• Term: from 2016 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 317946296

Infections with microbial pathogens represent a major global burden of disease. A multitude of complex molecular interactions between pathogens and host immune cells determine the course of ensuing inflammation. Immune sensing of pathogens during infections requires the detection of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs). Likewise, non-infectious injury results in the release of danger-associated molecular patterns (DAMPs) as endogenous ligands for PRRs. Here, we postulate that polyphosphates (PolyP), an undefined class of inorganic chain-shaped molecules in all living organisms, act as important and potent PAMPs during infection. To a lesser extend PolyP may also act as DAMPs during tissue injury. Long-chain PolyP (=PAMPs) are accumulated in bacteria, whereas platelets release short-chain PolyP (=DAMPs). Our preliminary data suggest that PolyP are potent modulators of macrophage functions and lung inflammation with their potency depending on chain length. We propose to characterize the effects of PolyP (in dependency of chain length) in resting and LPS/TLR4-activated macrophages by studying cytokine release, reactive oxygen species, nitric oxide, phagocytosis, chemotaxis and M1/M2 polarization. Furthermore, the modulation of gene expression by PolyP will be investigated in the whole transcriptome of macrophages using RNA next-generation sequencing. Gram-negative bacteria with genetic deficiency or over-expression of PolyP will be studied in murine pneumonia with or without concomitant depletion of macrophages (LysM-Cre iDTR mice). To identify the currently unknown PRRs that enable macrophages to detect PolyP, an affinity purification of PolyP-binding proteins followed by quantitative mass spectrometry is planned. These investigations will be complemented by functional screenings and imaging of PolyP-binding proteins as well as studies on PolyP-induced signaling pathways.The proposed studies will contribute to a better understanding of the host-pathogen interactions during bacterial infections. These findings may be helpful for the development of novel therapeutic interventions for infection-associated inflammatory diseases in future.

• DFG Programme: Research Grants
• Cooperation Partner: Professor Dr. Stefan Tenzer