Mechanisms in Sepsis
Posted by: Postdoc positions by NIH
Posted date: 2017-Apr-19
The focus of the lab is based upon a critical health issue in children with sepsis arising from dysregulated heme metabolism and resulting in impaired immune function. Sepsis phenotype manifests as an emergent property of invasive infection and host response and leads to significant morbidity and mortality in children. At least ½ of critically ill children in the US receive a RBC transfusion during their ICU stay. Mounting evidence from models of infection and from humans with sepsis indicate that RBC transfusion is associated with altered immunity and worsened outcome, though the specific mechanism for this observation is unknown. Notably, all transfusion, to a degree, leads to intravascular hemolysis; in prior work with a canine sepsis model, we have shown that plasma hemoglobin (Hb) and its metabolites, in synergy with infection, amplify organ failure and increase mortality. This project will focus upon a Hb metabolite in plasma, cell-free heme (CFH). Dysregulated heme metabolism is known to influence immunity and is newly appreciated to activate Toll-Like Receptor (TLR-4) as a damage associated molecular pattern (DAMP). With transfusion, decompartmentalized RBC contents may therefore directly influence host innate immune signaling by priming TLR-4. Classically the innate immune system would be most affected; however such TLR-4 priming may also have downstream impact upon adaptive immune responses, demonstrating broad consequences of heme-TLR-4 interaction. Thus, in children with sepsis receiving RBC transfusion, we hypothesize that there is a causal relationship between plasma CFH and altered innate immunity (possibly via TLR-4 priming) leading to amplified/persisting inflammation and worsened outcome. We are interested in additionally understanding via an exploratory study of altered adaptive immunity from heme-TLR-4 priming as an alternative/related explanation for the adverse impact of transfusion during infection.
A fellow with immunology background, preferably some biochemistry/hematology background. Also, background with mice and human samples would be a strength.
Please send your CVs to Kenneth Remy as an initial step.
Kenneth E. Remy, M.D., M.H.Sc.
Critical Care Medicine