Heme drives hemolysis-induced susceptibility to infection via disruption of phagocyte functions

Abstract : Hemolysis drives susceptibility to bacterial infections and predicts poor outcome from sepsis. These detrimental effects are commonly considered to be a consequence of heme-iron serving as a nutrient for bacteria. We employed a Gram-negative sepsis model and found that elevated heme levels impaired the control of bacterial proliferation independently of heme-iron acquisition by pathogens. Heme strongly inhibited phagocytosis and the migration of human and mouse phagocytes by disrupting actin cytoskeletal dynamics via activation of the GTP-binding Rho family protein Cdc42 by the guanine nucleotide exchange factor DOCK8. A chemical screening approach revealed that quinine effectively prevented heme effects on the cytoskeleton, restored phagocytosis and improved survival in sepsis. These mechanistic insights provide potential therapeutic targets for patients with sepsis or hemolytic disorders.
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https://hal.umontpellier.fr/hal-02298342
Contributeur : Anthony Herrada <>
Soumis le : jeudi 26 septembre 2019 - 16:27:16
Dernière modification le : vendredi 27 septembre 2019 - 01:22:43

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Rui Martins, Julia Maier, Anna-Dorothea Gorki, Kilian Huber, Omar Sharif, et al.. Heme drives hemolysis-induced susceptibility to infection via disruption of phagocyte functions. Nature Immunology, Nature Publishing Group, 2016, 17 (12), pp.1361-1372. ⟨10.1038/ni.3590⟩. ⟨hal-02298342⟩

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