Despite advances in antibiotic therapy, there is a significant need for more efficacious treatments of severe bacterial infections. The host responds to bacterial infection by activating the innate immune system to clear pathogen by phagocytic and killing mechanisms, resolve inflammation and return to homeostasis. In sepsis, activation of host response causes massive inflammation as well as a later paradoxical dysregulated inflammatory response where the host is immunocompromised and is susceptible to secondary infections. Specialized Pro-resolving Mediators (SPMs) are endogenously produced lipid mediators with infection resolution activity. A recent report showed that there was a temporal difference in release of different SPMs where early increase of Resolvins (Rvs) was associated with infection resolution. We and others show that SPMs, such as Lipoxin A4 (LXA4), and Rvs increased survival, decreased systemic inflammatory response and reduced bacteria load in cecal ligation and puncture (CLP) sepsis or other models of bacterial infection. We obtained evidence that LXA4 increased Fc? receptor1 (Fc?R1) dependent neutrophil phagocytic ability in CLP- sepsis while Rvs D1 and D2 increased human monocyte phagocytosis of Pseudomonas aeruginosa (P. aeruginosa) suggesting that SPMs can promote host defense to clear pathogen in sepsis. Quorum sensing is a cell density dependent mechanism which regulates expression and release of bacterial virulence factors. We have evidence that LXA4 inhibits binding of the bacterial quorum sensor 3-oxo- C12 HSL in P. aeruginosa with a potency approximately 1000-fold greater than known quorum sensing inhibitors. LXA4 reduced release of the exotoxin - pyocyanin which suggests that LXA4 may reduce bacterial virulence by quorum sensing inhibition. This is the first evidence that an endogenously produced compound can both augment host defense and directly reduce bacterial virulence. Therefore, we hypothesize that SPMs promote infection resolution by enhancing host defense and reducing bacterial virulence.
3 Specific Aims are proposed.
In AIM 1 we will test the hypothesis that SPMs enhance host defense to resolve infection in the 2-hit model of CLP sepsis with secondary Pseudomonas lung infection.
In AIM 2 we will test the hypothesis that the cellular mechanism of SPM enhanced antimicrobial leukocyte function is by promoting activity Rho GTPases and differentiation of monocytes to a pro-resolution phenotype.
In AIM 3 we will determine if SPMs inhibit quorum sensing and reduce bacterial virulence. We believe investigation of SPM mediated mechanisms of antimicrobial activity may have broad applications in bacterial infections and may contribute to new treatments.
Relevant Statement Despite advances in antibacterial therapy, complications from sepsis cause high mortality. The proposal will address how compounds termed Specialized Pro-resolving Mediators (SPMs) that can better resolve infection by promoting host defense and reducing bacterial virulence.
