2A)

2A). sepsis, Clorprenaline HCl meningitis and/or death. In pregnant woman may cross the placenta and infect the fetus, causing miscarriage, stillbirth or neonatal meningitis. Although cases of listeriosis are relatively uncommon, the mortality rate (20C30%) is much higher than that of more common foodborne illnesses like salmonellosis. As a consequence, is the third leading cause of death from food poisoning in the United States (2). Ultimate clearance of is dependent on CD4+ and CD8+ lymphocytes (3, 4). However, a robust innate immune reaction must precede the lymphocyte response to provide early Clorprenaline HCl containment and initiate adaptive immunity. For example, studies in knockout mice have revealed that TNF-, IFN- and IL-6 are required early in the course of infection for mobilization and activation of neutrophils, monocytes and macrophages (5C8). Although the type 2 interferon, IFN-, is critical in providing early host protection to growth. For example, mice deficient in the type 1 IFN receptor IFNAR1 are highly protected against in a type 1 IFN-dependent fashion (14). A major downstream target of type 1 IFN is TNF-related apoptosis-inducing ligand (TRAIL). A member of the TNF superfamily, TRAIL is a well-recognized IFN response gene (15). It induces cell death by binding to the death receptors DR4 and DR5. TRAIL expression is induced during infection in a type 1 IFN-dependent fashion primarily on the surface of NK cells (9, 16, 17). TRAIL?/? mice resemble IFNAR?/? mice in their enhanced containment of and reduced splenocyte depletion (16, 17). An ancient and powerful arm of innate immunity is the complement system. triggers the alternative pathway of complement activation, resulting in its opsonization by C3b and release of the complement anaphylatoxins C3a and C5a (18C20). Several studies have shown an important role for C3 and its cleavage polypeptides in the host response to (19C24). In contrast, little is known about the contribution of C5 and its major activation fragments C5a and C5b. The A/J mouse is one of the most susceptible strains to infection with (25). This susceptibility is largely due to the absence of C5 protein caused by a 2-bp gene deletion in the 5-exon of the structural gene encoding murine C5 (Hc locus) (26). The C5b fragment that initiates Rabbit Polyclonal to OR4F4 the formation of the C5b-9 complex is unlikely to be Clorprenaline HCl a factor in this susceptibility as Gram positive bacteria are protected against membrane attack complex (MAC)-mediated lysis by their thick layer of peptidoglycan (27). C5a is a 74 Clorprenaline HCl amino acid peptide that exerts its biological effects through a G-protein coupled Clorprenaline HCl receptor, C5aR1 (28). Classically described as an anaphylatoxin because of its ability to cause vasodilatation, histamine release and smooth muscle contraction, C5a is widely considered to be a pro-inflammatory molecule. This stems from its anaphylactic and chemotactic properties as well as its ability to enhance the expression of inflammatory cytokines like TNF-, IL-6 and IL-1 (29C31). Accordingly, it seemed plausible that C5a might provide protection against by promoting the expression of cytokines needed for the early cellular immune response. To test this hypothesis we utilized a model of systemic infection in WT and C5aR1?/? mice. Surprisingly, we found that while C5aR1?/? mice are highly susceptible to systemic infection through a previously unknown function of C5aR1–the suppression of type 1 IFN expression. Materials and Methods Mice.