Format

Send to

Choose Destination
Nat Immunol. 2016 Dec;17(12):1361-1372. doi: 10.1038/ni.3590. Epub 2016 Oct 31.

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

Author information

1
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
2
Department of Medicine I, Laboratory of Infection Biology, Medical University of Vienna, Vienna, Austria.
3
Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.
4
Department of Pathology, Medical University of Vienna, Vienna, Austria.
5
IST Austria (Institute of Science and Technology Austria), Klosterneuburg, Austria.
6
Clinical Department of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Vienna, Austria.
7
Department of Laboratory Medicine and Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA.
8
Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.

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.

PMID:
27798618
DOI:
10.1038/ni.3590
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center