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

Rui Martins, Julia Maier, Anna Dorothea Gorki, Kilian V.M. Huber, Omar Sharif, Philipp Starkl, Simona Saluzzo, Federica Quattrone, Riem Gawish, Karin Lakovits, Michael C. Aichinger, Branka Radic-Sarikas, Charles Hugues Lardeau, Anastasiya Hladik, Ana Korosec, Markus Brown, Kari Vaahtomeri, Michelle Duggan, Dontscho Kerjaschki, Harald EsterbauerJacques Colinge, Stephanie C. Eisenbarth, Thomas Decker, Keiryn L. Bennett, Stefan Kubicek, Michael Sixt, Giulio Superti-Furga, Sylvia Knapp*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

80 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1361-1372
Number of pages12
JournalNature Immunology
Volume17
Issue number12
DOIs
StatePublished - Dec 1 2016
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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