title: Heme drives hemolysis-induced susceptibility to infection via disruption of phagocyte functions.
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.
authors: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.|Department of Medicine I, Laboratory of Infection Biology, Medical University of Vienna, Vienna, Austria.
authors: Rui
authors: R
authors: Martins
authors: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.|Department of Medicine I, Laboratory of Infection Biology, Medical University of Vienna, Vienna, Austria.
authors: Julia
authors: http://orcid.org/0000-0001-9814-523X
authors: J
authors: Maier
authors: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.|Department of Medicine I, Laboratory of Infection Biology, Medical University of Vienna, Vienna, Austria.
authors: Anna-Dorothea
authors: AD
authors: Gorki
authors: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors: Kilian V M
authors: http://orcid.org/0000-0002-1103-5300
authors: KV
authors: Huber
authors: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.|Department of Medicine I, Laboratory of Infection Biology, Medical University of Vienna, Vienna, Austria.
authors: Omar
authors: O
authors: Sharif
authors: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.|Department of Medicine I, Laboratory of Infection Biology, Medical University of Vienna, Vienna, Austria.
authors: Philipp
authors: P
authors: Starkl
authors: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.|Department of Medicine I, Laboratory of Infection Biology, Medical University of Vienna, Vienna, Austria.
authors: Simona
authors: S
authors: Saluzzo
authors: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.|Department of Medicine I, Laboratory of Infection Biology, Medical University of Vienna, Vienna, Austria.
authors: Federica
authors: F
authors: Quattrone
authors: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.|Department of Medicine I, Laboratory of Infection Biology, Medical University of Vienna, Vienna, Austria.
authors: Riem
authors: R
authors: Gawish
authors: Department of Medicine I, Laboratory of Infection Biology, Medical University of Vienna, Vienna, Austria.
authors: Karin
authors: K
authors: Lakovits
authors: Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.
authors: Michael C
authors: MC
authors: Aichinger
authors: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors: Branka
authors: B
authors: Radic-Sarikas
authors: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors: Charles-Hugues
authors: CH
authors: Lardeau
authors: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.|Department of Medicine I, Laboratory of Infection Biology, Medical University of Vienna, Vienna, Austria.
authors: Anastasiya
authors: A
authors: Hladik
authors: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.|Department of Medicine I, Laboratory of Infection Biology, Medical University of Vienna, Vienna, Austria.
authors: Ana
authors: A
authors: Korosec
authors: Department of Pathology, Medical University of Vienna, Vienna, Austria.
authors: Markus
authors: M
authors: Brown
authors: IST Austria (Institute of Science and Technology Austria), Klosterneuburg, Austria.
authors: Kari
authors: K
authors: Vaahtomeri
authors: IST Austria (Institute of Science and Technology Austria), Klosterneuburg, Austria.
authors: Michelle
authors: M
authors: Duggan
authors: Department of Pathology, Medical University of Vienna, Vienna, Austria.
authors: Dontscho
authors: D
authors: Kerjaschki
authors: Clinical Department of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Vienna, Austria.
authors: Harald
authors: H
authors: Esterbauer
authors: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors: Jacques
authors: J
authors: Colinge
authors: Department of Laboratory Medicine and Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors: Stephanie C
authors: SC
authors: Eisenbarth
authors: Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.
authors: Thomas
authors: T
authors: Decker
authors: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors: Keiryn L
authors: http://orcid.org/0000-0001-9356-7708
authors: KL
authors: Bennett
authors: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors: Stefan
authors: http://orcid.org/0000-0003-0855-8343
authors: S
authors: Kubicek
authors: IST Austria (Institute of Science and Technology Austria), Klosterneuburg, Austria.
authors: Michael
authors: M
authors: Sixt
authors: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.|Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
authors: Giulio
authors: G
authors: Superti-Furga
authors: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.|Department of Medicine I, Laboratory of Infection Biology, Medical University of Vienna, Vienna, Austria.
authors: Sylvia
authors: http://orcid.org/0000-0001-9016-5244
authors: S
authors: Knapp
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D003599:Cytoskeleton / Q000378:metabolism; D005260:Female; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy / Q000276:immunology*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006418:Heme / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000235:genetics; D006461:Hemolysis / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D057131:Immune Evasion; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000382:microbiology; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010587:Phagocytosis / Q000187:drug effects; D011803:Quinine / Q000627:therapeutic use; D000067996:RAW 264.7 Cells; D018805:Sepsis / Q000188:drug therapy / Q000276:immunology*; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; C545324:Dock8 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D008565:Membrane Proteins; D006418:Heme; D011803:Quinine; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D020764:cdc42 GTP-Binding Protein