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 Esterbauer; Jacques Colinge; Stephanie C. Eisenbarth; Thomas Decker; Keiryn L. Bennett; Stefan Kubicek; Michael Sixt; Giulio Superti-Furga; Sylvia Knapp

doi:10.1038/ni.3590

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

Medicine, Allergy Division

Research output: Contribution to journal › Article › peer-review

121 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 language	English (US)
Pages (from-to)	1361-1372
Number of pages	12
Journal	Nature Immunology
Volume	17
Issue number	12
DOIs	https://doi.org/10.1038/ni.3590
State	Published - Dec 1 2016

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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Martins, R., Maier, J., Gorki, A. D., Huber, K. V. M., Sharif, O., Starkl, P., Saluzzo, S., Quattrone, F., Gawish, R., Lakovits, K., Aichinger, M. C., Radic-Sarikas, B., Lardeau, C. H., Hladik, A., Korosec, A., Brown, M., Vaahtomeri, K., Duggan, M., Kerjaschki, D., ... Knapp, S. (2016). Heme drives hemolysis-induced susceptibility to infection via disruption of phagocyte functions. Nature Immunology, 17(12), 1361-1372. https://doi.org/10.1038/ni.3590

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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.",

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

year = "2016",

month = dec,

day = "1",

doi = "10.1038/ni.3590",

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Martins, R, Maier, J, Gorki, AD, Huber, KVM, Sharif, O, Starkl, P, Saluzzo, S, Quattrone, F, Gawish, R, Lakovits, K, Aichinger, MC, Radic-Sarikas, B, Lardeau, CH, Hladik, A, Korosec, A, Brown, M, Vaahtomeri, K, Duggan, M, Kerjaschki, D, Esterbauer, H, Colinge, J, Eisenbarth, SC, Decker, T, Bennett, KL, Kubicek, S, Sixt, M, Superti-Furga, G & Knapp, S 2016, 'Heme drives hemolysis-induced susceptibility to infection via disruption of phagocyte functions', Nature Immunology, vol. 17, no. 12, pp. 1361-1372. https://doi.org/10.1038/ni.3590

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T1 - Heme drives hemolysis-induced susceptibility to infection via disruption of phagocyte functions

AU - Martins, Rui

AU - Maier, Julia

AU - Gorki, Anna Dorothea

AU - Huber, Kilian V.M.

AU - Sharif, Omar

AU - Starkl, Philipp

AU - Saluzzo, Simona

AU - Quattrone, Federica

AU - Gawish, Riem

AU - Lakovits, Karin

AU - Aichinger, Michael C.

AU - Radic-Sarikas, Branka

AU - Lardeau, Charles Hugues

AU - Hladik, Anastasiya

AU - Korosec, Ana

AU - Brown, Markus

AU - Vaahtomeri, Kari

AU - Duggan, Michelle

AU - Kerjaschki, Dontscho

AU - Esterbauer, Harald

AU - Colinge, Jacques

AU - Eisenbarth, Stephanie C.

AU - Decker, Thomas

AU - Bennett, Keiryn L.

AU - Kubicek, Stefan

AU - Sixt, Michael

AU - Superti-Furga, Giulio

AU - Knapp, Sylvia

PY - 2016/12/1

Y1 - 2016/12/1

N2 - 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.

AB - 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.

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EP - 1372

JO - Nature Immunology

JF - Nature Immunology

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

Abstract

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