Sepsis develops when an initial, appropriate innate immune response to infection becomes amplified and dysregulated, so as to result in an acute and destructive systemic inflammatory reaction that, in its severest outcome, produces a vascular collapse and multiorgan failure (septic shock) which is often fatal. Bacterial sepsis culminating in septic shock is a significant and increasing cause of morbidity and mortality in the United States, and it is frequently due to infection with Gram negative bacteria. Although originally recognized as products of the innate immune response to viral infection, it is now known that type I interferons (IFN) (IFN-alpha and IFN-beta) are also secreted upon stimulation of immune cells with components of Gram negative bacteria, including lipopolysaccharide (LPS; a.k.a, endotoxin), which triggers Toll Receptor (TLR) 4, and certain DNA CpG motifs that trigger TLR9. An essential role for type I IFN in lethal sepsis is strongly suggested by the finding that IFN- beta deficient mice are resistant to LPS induced endotoxic shock. However, the mechanisms by which type I IFN contribute to lethal sepsis are unknown. Work in our laboratory has demonstrated that type I IFN can significantly enhance stimulated myeloid dendritic cell (DC) expression of multiple inflammatory cytokines implicated in mediating Gram negative sepsis: IL-1, IL-6, IFN-gamma, IL-18 and IL-12. Based on our findings, and work of others, we hypothesize that LPS/CpG-induced type I IFN are crucial mediators of Gram negative sepsis and septic shock, as a result of their ability to amplify monocyte/macrophage and DC inflammatory cytokine secretion. We propose that neutralization of type I IFN during sepsis will inhibit bacterial-induced inflammation and toxicity to such a degree as to prevent a fatal outcome. The goal of this proposal is to characterize the role of type I IFN in lethal toxic shock induced by Gram negative bacterial components. The role of type I IFN in regulating induction of both immune inflammatory cytokines and lethal toxic shock will be investigated in human and murine in vitro models (Specific Aim 1) and murine in vivo (Specific Aim 2) models of Gram negative, LPS/CpG, stimulation.
Specific Aim 3 will determine whether type I IFN neutralization by soluble recombinant vaccinia virus type I IFN receptor (B18R) is effective in preventing lethal LPS/CpG-induced toxic shock. The results of these studies will contribute to an understanding of the role of type I IFN during bacterial sepsis, and they will have a direct impact on the development of immunotherapies for the treatment of bacterial sepsis and septic shock.
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