Targeting Sepsis

Le Bonheur researcher Guoyun Chen, MD, PhD, has been awarded $1.9 million from the National Institutes of Health to fund sepsis research.

His project, titled “Targeting Siglec -9/E for therapy of sepsis,” will build on Chen’s prior work investigating the function of Siglecs in innate immune and inflammatory responses with the ultimate aim of identifying novel targets for sepsis therapy.

Sepsis, an extreme, dysregulated inflammatory host response to infection, is attributed to 250,000 deaths in the United States each year. More than 1.5 million cases of sepsis are reported, according to the Centers for Disease Control and Prevention.

Chen’s experimental approach centers on investigating the negative regulation of toll-like receptor (TLR) signaling. TLR signaling is a key pathway in sepsis pathogenesis and is responsible for much of the excessive inflammatory response. As many infectious agents express ligands for several TLRs, current therapies targeting individual receptors have proven ineffective.

Chen’s work aims to overcome these therapeutic limitations by simultaneously targeting multiple TLRs and dampening their downstream inflammatory signaling. Previously published data from the Chen Laboratory identified members of the sialic acid-binding immunoglobulin superfamily (Siglecs) as potential candidates for sepsis therapy. Studies using dendritic cells deficient in Siglec-E displayed increased inflammatory responses to all TLR ligands tested compared to cells containing Siglec-E. New preliminary experimental results suggest that Siglec-E negatively regulates all TLR4 by inducing TLR endocytosis and degradation, thereby terminating signaling downstream. With the NIH award, the Chen laboratory will now further study the mechanism by which this occurs and will explore novel therapeutic strategies using Siglec-E as a candidate for sepsis therapy.