João Arezes received the First Prize at the Department of Medicine Research Day and will present at the ASH Annual meeting
João Arezes, a visiting graduate student from the University of Porto, Portugal, was selected to receive a travel award to the American Society of Hematology meeting in New Orleans, December 7-10, 2013, to present his work on the role of hepcidin in host defense against Vibrio vulnificus, a gram-negative marine bacterium that causes flesh-eating disease and fulminant sepsis in patients with iron disorders (see abstract below).
João Arezes was also honored for related work at the Department of Medicine Research Day on October 5, 2013 where he won the First Prize for Students and Trainees, including a very generous financial award.
Hepcidin-Induced Hypoferremia Is a Host-Defense Mechanism Against Siderophilic BacteriaJoão Arezes1,2, Chun-Ling Jung1, Victoria Gabayan1, Erika Valore1, Tomas Ganz1, Yonca Bulut1* and Elizabeta Nemeth1*
1David Geffen School of Medicine at UCLA, Los Angeles, CA, USA and 2Graduate Program in Areas of Basic and Applied Biology, Abel Salazar Biomedical Sciences Institute, University of Porto, Porto, Portugal, *authors contributed equally.
Introduction: The iron-regulatory hormone hepcidin, a 25 amino acid peptide secreted by hepatocytes, is greatly increased during infection or inflammation, causing hypoferremia. Hypoferremia during infections has been proposed as a host defense mechanism that evolved to restrict iron availability for pathogen growth but specific support for this hypothesis has been lacking. Hereditary hemochromatosis, an iron overload disease caused by hepcidin deficiency, is associated with greatly increased risk of infections with siderophilic pathogens such as Vibrio vulnificus and Yersinia enterocolitica. Hepatic iron overload, high plasma iron concentrations and impaired hypoferremic response to infection could contribute to the susceptibility of hereditary hemochromatosis patients to infections with siderophilic bacteria. In this study we investigated the role of hepcidin-induced hypoferremia in murine resistance to Vibrio vulnificus infection.
Methods: In order to examine the effect of iron stores, plasma iron concentrations and inflammatory hypoferremia on susceptibility to infection, we fed wild type (WT) mice low (4ppm) or high (10,000ppm) iron diets, and hepcidin KO (Hamp1-/-) mice low or standard (270ppm) iron diets, to iron-deplete or iron-load them. The mice were infected with V. vulnificus (CMCP6 strain) by subcutaneous administration. We analyzed survival, CFU counts in blood and tissues, as well as iron and inflammatory parameters. In addition, we tested the host-protective effect of acute hypoferremia induced by the minihepcidin PR73, a hepcidin agonist developed in our laboratory.
|HAMP -/-||WILD TYPE|
|Iron depleted||Iron loaded||Iron depleted||Iron loaded|
Results: As expected, V. vulnificus growth and resulting host mortality was greatly enhanced in iron-loaded as compared to iron-depleted mice, in both WT and Hamp1-/- mice. Comparing WT to Hamp1-/- mice, both iron-loaded and iron-depleted Hamp1-/- mice had much higher mortality than either iron-loaded or iron-depleted WT when given the same number of bacteria. Relative to the number of injected bacterial CFU, Hamp1-/- mice had much higher post-infection bacterial counts in blood, liver and spleen. Furthermore, Hamp1-/- mice did not develop hypoferremia during infection whereas WT mice responded to the infection by acutely increasing plasma hepcidin concentration (within 6 h) and lowering serum iron (Table).
To isolate the role of hypoferremia, we next compared iron-loaded WT mice to iron-depleted Hamp1-/- mice. Despite lower hepatic iron stores (425±109 vs 112±81 μg/g) and identical baseline serum iron concentrations (65±4 vs 69±7 μM), iron-depleted Hamp1-/- mice were still much more susceptible to V. vulnificus infection than iron-loaded WT mice, with 1000-fold lower number of bacteria needed for lethal infection (1x103 CFU for Hamp1-/- vs 1x106 CFU for WT), suggesting that hepcidin-dependent hypoferremia is critical for the control of V. vulnificus infection.
Experimental induction of hypoferremia in Hamp1-/- mice by the administration of the minihepcidin PR73 prior to infection abated mortality from a lethal dose of V. vulnificus (103 CFUs: 25% vs 100% survival, p< 0.01, iron-depleted; 0% vs 80% survival, p<0.01, iron-loaded; 105 CFUs: 0% vs 100% survival, p< 0.01, iron-depleted; 0% vs 75% survival, p<0.05, iron-loaded) and dramatically reduced bacterial burden in blood and tissues. Minihepcidin treatment was life-saving even when administered 3h after infection to iron-overloaded Hamp1-/- mice (Figure).
Conclusion: Reactive hepcidin-induced hypoferremia after V. vulnificus infection restricts bacterial growth and helps protect the host from acute mortality. Timely administration of hepcidin agonists to hepcidin-deficient subjects may protect against morbidity and mortality from infections with siderophilic microorganisms.