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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.

Original publication

DOI

10.1038/ni.3590

Type

Journal article

Journal

Nat Immunol

Publication Date

12/2016

Volume

17

Pages

1361 - 1372

Keywords

Animals, Anti-Bacterial Agents, Cytoskeleton, Female, Gram-Negative Bacterial Infections, Guanine Nucleotide Exchange Factors, Heme, Heme Oxygenase-1, Hemolysis, Humans, Immune Evasion, Macrophages, Membrane Proteins, Mice, Mice, Inbred C57BL, Mice, Knockout, Phagocytosis, Quinine, RAW 264.7 Cells, Sepsis, cdc42 GTP-Binding Protein