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This study demonstrates that sTREM2, a soluble protein released from microglial cells and intestinal macrophages, can inhibit the formation of bacterial amyloid fibrils by the protein CsgA, which is essential for biofilm formation in disease-causing E. coli and other bacteria. The research shows that sTREM2 works at sub-stoichiometric concentrations by slowing the initial nucleation steps of amyloid formation rather than affecting fiber elongation, and successfully suppresses biofilm formation when added to bacterial cultures without affecting bacterial growth. These findings suggest that immune cells in the gut may use sTREM2 as a natural defense mechanism against bacterial amyloid production.
Why it matters
This research identifies a potential new approach for combating bacterial biofilms, which are notoriously difficult to treat and contribute to antibiotic resistance in urinary tract infections and other diseases. Understanding how the human immune system naturally inhibits bacterial amyloid formation could lead to novel therapeutic strategies for preventing or disrupting biofilm-associated infections.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Protein misfolding and aggregation, including amyloid fibril formation, underlie a large class of human diseases including prominent neurological disorders such as Alzheimer’s and Parkinson’s disease. A small number of human proteins have been identified that inhibit amyloidogenesis. One such protein is sTREM2, a soluble receptor liberated from microglia, the resident macrophages of the central nervous system. The extracellular domain of TREM2 is shed upon proteolytic cleavage to create sTREM2, which has previously been shown to inhibit amyloid-{beta} aggregation in vitro. TREM2 is also expressed by intestinal macrophages, which are known to directly bind the bacterial amyloid curli and mount cytokine responses upon exposure. Here we show that sTREM2 is a sub-stoichiometric inhibitor of CsgA amyloidogenesis, CsgA being the major protein component of curli that drives biofilm formation in uropathogenic Escherichia coli and many other proteobacteria. In vitro, sTREM2 potently and sub-stoichiometrically inhibited CsgA amyloidogenesis in a dose-dependent manner. Kinetic modeling indicated that sTREM2 slowed primary and secondary nucleation, rather than altering fiber elongation. When added exogenously to bacterial growth medium, sTREM2 significantly suppressed curli-dependent pellicle biofilm formation without affecting bacterial growth. These findings establish sTREM2 as a member of the small group of human proteins capable of inhibiting bacterial functional amyloidogenesis, suggesting that gut-resident TREM2-expressing macrophages, which are already known to interact with curli, may employ sTREM2 as a physiologically relevant defense against bacterial amyloid formation.