The studies proposed will focus on further elucidating mechanisms through which CD14 influences the inflammatory response.
Specific Aim 1 : To define the relative role of the CD14:LPS interaction in the shock response to bacterial pathogens posessing various virulence fqactors. We have previously shown that CD14-deficient mice are highly resistant to the lethal effects of LPS and E. Coli 0111. Our hypothesis is that some Gram-negative bacteria will induce shock predominently via the CD14:LPS pathway while other bacteria having different virulance factors will induce shock via CD14 independent mechanisms. To test this hypothesis, we will first study the shock response of CD14-deficient and normal mice to a well characterized panel of E. coli expressing defined virulence determinants. Next, we will test the role of the CD14:LPS interaction in a peritonitis model of shock induced by cecal ligation and puncture. Finally, we will use an oral model of shock to examine the role of CD14 in the response to intracellular organisms that use unique mechanisms to evade the host immune defense. These studies will expand our understanding of the relative roleof the CD14:LPS interaction in shock induced by bacteria and will begin to elucidate the mechanisms operating in CD14:LPS mediated shock versus CD14-independent shock.
Specific Aim 2 : To define the relative role of the CD14:LPS interaction in local infection. We believe that the mechanisms operating systemic models will also operateon the local level. That is, those bacteria which cause inflammation in CD!14-deficient mice will cause a local inflammatory response in CD14-/- mice, similar to that of normal mice; those bacteria which do not cause shock in CD14-deficient mice will not cause tissue damage and will be quickly cleared. The results from these experiments should complement those in the shock model and lead to an enhanced understandingf of the mechanisms regulating virulence of these bacteria and their role im imflammation.
Specific Aim 3 : To determine the role of soluble CD14 (sCD14) in septic shock and local inflammation induced by LPS and various bacteria (Gram-negative, Gram-positive). Studies suggest that there are two pathways for activation with LPS; One that stimulates via membrane CD14 and one that stimulates via another pathway and requires a complex of performance sites.
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