期刊
NATURE IMMUNOLOGY
卷 17, 期 12, 页码 1361-1372出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ni.3590
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资金
- Austrian Academy of Sciences
- Science Fund of the Austrian National Bank [14107]
- Austrian Science Fund FWF in the Infect-ERA framework [I1620 -B22]
- Austrian Science Fund (FWF) [I 1620, I 1674] Funding Source: researchfish
- Austrian Science Fund (FWF) [I1620, I1674] Funding Source: Austrian Science Fund (FWF)
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 DOCKS. 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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