Content area
Full Text
A RT I C L E S
Heme drives hemolysis-induced susceptibility to infection via disruption of phagocyte functions
Rui Martins1,2, Julia Maier1,2, Anna-Dorothea Gorki1,2, Kilian V M Huber1, Omar Sharif1,2, Philipp Starkl1,2, Simona Saluzzo1,2, Federica Quattrone1,2, Riem Gawish1,2,9, Karin Lakovits2, Michael C Aichinger3,
Branka Radic-Sarikas1, Charles-Hugues Lardeau1, Anastasiya Hladik1,2, Ana Korosec1,2, Markus Brown4, Kari Vaahtomeri5, Michelle Duggan5, Dontscho Kerjaschki4, Harald Esterbauer6, Jacques Colinge1, Stephanie C Eisenbarth7, Thomas Decker3, Keiryn L Bennett1, Stefan Kubicek1, Michael Sixt5, Giulio Superti-Furga1,8
& Sylvia Knapp1,2
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.
Intravascular hemolysis is a serious complication that accompanies severe inflammatory conditions such as sepsis, is an established complication of hemolytic disorders such as sickle cell disease (SCD), malaria infection or beta-thalassemia, and affects millions of people worldwide15. In these disorders, extensive hemolysis leads to the release of the heme moiety from hemoglobin, which can rapidly exhaust the bodys heme-scavenging capacity and results in high amounts of circulating heme58. Excess heme is important for driving disease pathology, primarily as a result of its pro-oxidant properties, which sensitize cells to the cytopathic effects of inflammatory mediators such as tumor necrosis factor (TNF)911. These effects have been demonstrated in models of polymicrobial sepsis and noncerebral malaria, in which mice lacking the heme-degrading enzyme HO-1 (heme oxygenase-1) have increased disease severity and succumb to organ failure4,12.
However, reduced disease tolerance cannot explain the substantially increased susceptibility to bacterial infections in people with hemolytic disorders such as SCD13, beta-thalassemia14 and malaria15,16. Mortality rates of 40% in children with SCD1 reflect the tremendous threat of bacterial infections in these...