Sepsis is a systemic inflammatory response syndrome initiated by infection. Most cases of septic shock are caused by Gram-negative bacteria, including Escherichia coli (E. coli), which remains one of the most common pathogens leading to sepsis. Understanding the mechanisms by which the mammalian immune system differentially responds to infection by Gram-negative and Gram-positive bacteria will place us in a better position to treat or prevent sepsis. Members of the sialic acid-binding immunoglobulin-like lectin family (Siglecs) are cell surface receptors that negatively regulate the response to infection by binding or taking up sialylated pathogens; however, most pathogens are not sialylated. We previously published a study in which we used nonsialylated bacteria to show that Siglec-E knockout (SiglecE-/-) mice exhibited higher mortality than wild-type (WT) mice following infection by Gram-negative but not Gram-positive bacteria. Better survival in WT mice depended on more efficient clearance of Gram-negative than Gram-positive bacteria. Moreover, infection with Gram-negative E. coli strains 25922 and DH5α induced the expression of Siglec-E, which promoted production of reactive oxygen species (ROS). In contrast, infection with Gram-positive bacteria Staphylococcus aureus or Listeria monocytogenes reduced expression of Siglec-E, which inhibited production of ROS. Based on these findings, we designed this project to: 1) Elucidate the molecular mechanisms of Siglec-E in bacterial clearance; 2) Dissect the molecular mechanisms underlying differential regulation of innate immune response during infection with Gram-positive and Gram-negative bacteria by controlling Siglec-E; 3) Evaluate Siglec-E as a therapeutic target for the treatment of bacterial sepsis by using CLP. These studies will not only reveal the molecular mechanisms of the novel role of Siglec-E in bacterial clearance but also provide novel approaches toward treatment of bacterial induced-sepsis.