Sepsis is generally defined as a systemic inflammatory response syndrome triggered by microbial infection. Severe sepsis (septic shock) can be a life-threatening condition, and approximately 200,000 deaths annually are attributed to sepsis in the US alone. Despite the availability of the treatment for sepsis with antibiotic therapy, inotropes, fluid resuscitation and end-organ support, there is a critical need for targeted and effective sepsis therapy to reduce mortality from this disease. The Toll-like receptor (TLR) family is responsible for detecting pathogens and inducing innate and adaptive immunity, while sialic acid-binding immunoglobulin superfamily lectin receptors (Siglecs) provide negative regulation for the immune response. Recently, we reported extensive and direct interactions between these pattern recognition receptors (PRRs). The most promiscuous TLR binders were human Siglecs 5 and 9. We have observed that the dendritic cells (DCs) from Siglece (mouse homologue of the human Siglec-9) deficient mice demonstrated increased responses to all TLR ligands tested and that Siglec-E negatively regulates the activation of TLR4 by controlling its endocytosis, suggesting that Siglec-E may play an important role in TLR-related sepsis development. To elucidate the function of this novel pathway in sepsis development, our research focuses on the molecular mechanism of the Siglec-E-TLR interaction in controlling bacterial infection-induced sepsis. Thus, in this project, we plan to: 1) examine the underlying molecular mechanism by which Siglec-E regulates infection-induced TLRs endocytosis; 2) Functional analysis of Siglec-E- mediated TLRs endocytosis and degradation during infection; 3) explore novel therapeutic strategies for the treatment of sepsis. These studies will not only reveal the molecular mechanism of the Siglec-E-TLRs pathway in infection-induced TLRs endocytosis, but will also translate our knowledge from basic science research into the clinical treatment of sepsis.
Despite the availability of antibiotics and other therapies, the mortality and hospitalization of patients with severe sepsis increased rapidly, causing approximately 200,000 annual deaths in the United States alone. Our proposed studies are designed to delineate the molecular mechanisms of sepsis development and aim to provide a novel therapeutic approach for septic shock.
