Heme drives hemolysis-induced susceptibility to infection via disruption of phagocyte functions. Martins, R., Maier, J., Gorki, A., D., Huber, K., V., 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., Esterbauer, H., Colinge, J., Eisenbarth, S., C., Decker, T., Bennett, K., L., Kubicek, S., Sixt, M., Superti-Furga, G., & Knapp, S. Nature Immunology, 2016.
abstract   bibtex   
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.
@article{
 title = {Heme drives hemolysis-induced susceptibility to infection via disruption of phagocyte functions},
 type = {article},
 year = {2016},
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 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.},
 bibtype = {article},
 author = {Martins, Rui and Maier, Julia and Gorki, Anna Dorothea and Huber, Kilian V.M. and Sharif, Omar and Starkl, Philipp and Saluzzo, Simona and Quattrone, Federica and Gawish, Riem and Lakovits, Karin and Aichinger, Michael C. and Radic-Sarikas, Branka and Lardeau, Charles Hugues and Hladik, Anastasiya and Korosec, Ana and Brown, Markus and Vaahtomeri, Kari and Duggan, Michelle and Kerjaschki, Dontscho and Esterbauer, Harald and Colinge, Jacques and Eisenbarth, Stephanie C. and Decker, Thomas and Bennett, Keiryn L. and Kubicek, Stefan and Sixt, Michael and Superti-Furga, Giulio and Knapp, Sylvia},
 journal = {Nature Immunology}
}
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