--- _id: '1142' abstract: - lang: eng text: 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. acknowledgement: 'Y. Fukui (Medical Institute of Bioregulation, Kyushu University) and J. Stein (Theodor Kocher Institute, University of Bern) are acknowledged for providing the DOCK8 deficient bone marrow. and H. Häcker (St. Judes Children''s Research Hospital) for providing the ERHBD-HoxB8-encoding retroviral construct. pSpCas9(BB)-2a-Puro (PX459) was a gift from F. Zhang (Massachusetts Institute of Technology) (Addgene plasmid # 48139) and pGRG36 was a gift from N. Craig (Johns Hopkins University School of Medicine) (Addgene plasmid # 16666). LifeAct-GFP-encoding retrovirus was kindly provided by A. Leithner (Institute of Science and Technology Austria). pSIM8 and TKC E. coli were gifts from D.L. Court (Center for Cancer Research, National Cancer Institute). We acknowledge M. Gröger and S. Rauscher for excellent technical support (Core imaging facility, Medical University of Vienna). We thank D.P. Barlow and L.R. Cheever for critical reading of the manuscript. This work was supported by the Austrian Academy of Sciences, the Science Fund of the Austrian National Bank (14107) and the Austrian Science Fund FWF (I1620-B22) in the Infect-ERA framework (to S.Knapp).' author: - first_name: Rui full_name: Martins, Rui last_name: Martins - first_name: Julia full_name: Maier, Julia last_name: Maier - first_name: Anna full_name: Gorki, Anna last_name: Gorki - first_name: Kilian full_name: Huber, Kilian last_name: Huber - first_name: Omar full_name: Sharif, Omar last_name: Sharif - first_name: Philipp full_name: Starkl, Philipp last_name: Starkl - first_name: Simona full_name: Saluzzo, Simona last_name: Saluzzo - first_name: Federica full_name: Quattrone, Federica last_name: Quattrone - first_name: Riem full_name: Gawish, Riem last_name: Gawish - first_name: Karin full_name: Lakovits, Karin last_name: Lakovits - first_name: Michael full_name: Aichinger, Michael last_name: Aichinger - first_name: Branka full_name: Radic Sarikas, Branka last_name: Radic Sarikas - first_name: Charles full_name: Lardeau, Charles last_name: Lardeau - first_name: Anastasiya full_name: Hladik, Anastasiya last_name: Hladik - first_name: Ana full_name: Korosec, Ana last_name: Korosec - first_name: Markus full_name: Brown, Markus id: 3DAB9AFC-F248-11E8-B48F-1D18A9856A87 last_name: Brown - first_name: Kari full_name: Vaahtomeri, Kari id: 368EE576-F248-11E8-B48F-1D18A9856A87 last_name: Vaahtomeri orcid: 0000-0001-7829-3518 - first_name: Michelle full_name: Duggan, Michelle id: 2EDEA62C-F248-11E8-B48F-1D18A9856A87 last_name: Duggan - first_name: Dontscho full_name: Kerjaschki, Dontscho last_name: Kerjaschki - first_name: Harald full_name: Esterbauer, Harald last_name: Esterbauer - first_name: Jacques full_name: Colinge, Jacques last_name: Colinge - first_name: Stephanie full_name: Eisenbarth, Stephanie last_name: Eisenbarth - first_name: Thomas full_name: Decker, Thomas last_name: Decker - first_name: Keiryn full_name: Bennett, Keiryn last_name: Bennett - first_name: Stefan full_name: Kubicek, Stefan last_name: Kubicek - first_name: Michael K full_name: Sixt, Michael K id: 41E9FBEA-F248-11E8-B48F-1D18A9856A87 last_name: Sixt orcid: 0000-0002-6620-9179 - first_name: Giulio full_name: Superti Furga, Giulio last_name: Superti Furga - first_name: Sylvia full_name: Knapp, Sylvia last_name: Knapp citation: ama: Martins R, Maier J, Gorki A, et al. Heme drives hemolysis-induced susceptibility to infection via disruption of phagocyte functions. Nature Immunology. 2016;17(12):1361-1372. doi:10.1038/ni.3590 apa: Martins, R., Maier, J., Gorki, A., Huber, K., Sharif, O., Starkl, P., … Knapp, S. (2016). Heme drives hemolysis-induced susceptibility to infection via disruption of phagocyte functions. Nature Immunology. Nature Publishing Group. https://doi.org/10.1038/ni.3590 chicago: Martins, Rui, Julia Maier, Anna Gorki, Kilian Huber, Omar Sharif, Philipp Starkl, Simona Saluzzo, et al. “Heme Drives Hemolysis-Induced Susceptibility to Infection via Disruption of Phagocyte Functions.” Nature Immunology. Nature Publishing Group, 2016. https://doi.org/10.1038/ni.3590. ieee: R. Martins et al., “Heme drives hemolysis-induced susceptibility to infection via disruption of phagocyte functions,” Nature Immunology, vol. 17, no. 12. Nature Publishing Group, pp. 1361–1372, 2016. ista: Martins R, Maier J, Gorki A, Huber K, Sharif O, Starkl P, Saluzzo S, Quattrone F, Gawish R, Lakovits K, Aichinger M, Radic Sarikas B, Lardeau C, Hladik A, Korosec A, Brown M, Vaahtomeri K, Duggan M, Kerjaschki D, Esterbauer H, Colinge J, Eisenbarth S, Decker T, Bennett K, Kubicek S, Sixt MK, Superti Furga G, Knapp S. 2016. Heme drives hemolysis-induced susceptibility to infection via disruption of phagocyte functions. Nature Immunology. 17(12), 1361–1372. mla: Martins, Rui, et al. “Heme Drives Hemolysis-Induced Susceptibility to Infection via Disruption of Phagocyte Functions.” Nature Immunology, vol. 17, no. 12, Nature Publishing Group, 2016, pp. 1361–72, doi:10.1038/ni.3590. short: R. Martins, J. Maier, A. Gorki, K. Huber, O. Sharif, P. Starkl, S. Saluzzo, F. Quattrone, R. Gawish, K. Lakovits, M. Aichinger, B. Radic Sarikas, C. Lardeau, A. Hladik, A. Korosec, M. Brown, K. Vaahtomeri, M. Duggan, D. Kerjaschki, H. Esterbauer, J. Colinge, S. Eisenbarth, T. Decker, K. Bennett, S. Kubicek, M.K. Sixt, G. Superti Furga, S. Knapp, Nature Immunology 17 (2016) 1361–1372. date_created: 2018-12-11T11:50:22Z date_published: 2016-12-01T00:00:00Z date_updated: 2021-01-12T06:48:36Z day: '01' department: - _id: MiSi - _id: PeJo doi: 10.1038/ni.3590 intvolume: ' 17' issue: '12' language: - iso: eng main_file_link: - open_access: '1' url: https://ora.ox.ac.uk/objects/uuid:f53a464e-1e5b-4f08-a7d8-b6749b852b9d month: '12' oa: 1 oa_version: Submitted Version page: 1361 - 1372 publication: Nature Immunology publication_status: published publisher: Nature Publishing Group publist_id: '6216' quality_controlled: '1' scopus_import: 1 status: public title: Heme drives hemolysis-induced susceptibility to infection via disruption of phagocyte functions type: journal_article user_id: 3E5EF7F0-F248-11E8-B48F-1D18A9856A87 volume: 17 year: '2016' ...