Friday, 18 August 2017 10:08

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

doi:10.1038/ni.3590

 

Rui Martins1,3, Julia Maier1,3, Anna-Dorothea Gorki1,3, Kilian V M Huber1, Omar Sharif1,3, Philipp Starkl1,3, Simona Saluzzo1,3, Federica Quattrone1,3, Riem Gawish1,3, Karin Lakovits3, Michael C Aichinger2, Branka Radic-Sarikas1, Charles-Hugues Lardeau1, Anastasiya Hladik1,3, Ana Korosec1,3, Markus Brown4, Kari Vaahtomeri5, Michelle Duggan5, Dontscho Kerjaschki4, Harald Esterbauer6, Jacques Colinge1, Stephanie C Eisenbarth7, Thomas Decker2, Keiryn L Bennett1, Stefan Kubicek1, Michael Sixt5, Giulio Superti-Furga1, Sylvia Knapp1,3

 

1CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.

2Max F. Perutz Laboratories, University of Vienna, Vienna, Austria

3Department of Medicine I, Laboratory of Infection Biology, Medical University of Vienna, Vienna, Austria.

4Department of Pathology, Medical University of Vienna, Vienna, Austria.

5Institute of Science and Technology Austria, Klosterneuburg, Austria.

6Clinical Department of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Vienna, Austria.

7Department of Laboratory Medicine and Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA.

 

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.