The rise of multidrug resistant bacteria, the increasingly invasive modern medical practices and the increased awareness of the bioterrorist threat, have greatly contributed to the quest for novel anti-pathogen therapies with improved pharmacology and potency. In vertebrates, conserved non self molecular signatures produced by pathogens (pathogen associated molecular patterns, PAMPs) are recognized by a dedicated array of germ line encoded soluble and cell associated pattern recognition receptors (PRR). Our goal is to target pathogens and their products using artificial antibodies (anti-pathogen immunoadhesins, APIs) consisting of the pathogen binding portion of selected PRR and the Fc portion of immunoglobulins. The PRRs were evolutionary selected to recognize a broad spectrum of pathogen derived chemicals, therefore we hypothesize that the use of a single API, or the combination of different ones, may help to resolve infection. APIs which bind to the invading microorganisms will provide additional anchorage sites for both components of the lytic complement system and Fc receptors. These anchorage sites will promote C-mediated pathogen killing, enhance phagocytosis and therefore aid in bacterial clearance. APIs are predicted to function as novel pathogen-host extracellular adapters, and are expected to accelerate responses that normally take weeks to occur (generation of highly specific antibodies). The purpose of this R21 application is to explore a potential role for an arsenal of anti-pathogen immunoadhesins as a novel class of antibiotics/bacteriostatics alone or in combination with conventional antibacterial chemotherapy. We will focus on the characterization and production of immunoadhesins comprising a C-terminal Fc portion along with TLR2, TLR5, CD14, BPI and Factor H as pathogen recognition modules. These molecules have been engineered in our lab and proven to be valuable in a) binding to purified PAMPs. b) binding to bacteria (Yersinia pestis) and c) promoting complement mediated killing (Neisseria gonorrhoeae). The impact on human health of this alternative antibacterial approach is multifold and may eventually represent a valid support, if not an alternative, to conventional antibacterial chemotherapy, for which several bacterial strains acquired resistance. APIs can be useful as prophylactic (e.g. before a major surgery) or therapeutic agents (e.g. during septicemia, or after exposure to a biological warfare agent). An additional advantage of these biologic response modifiers is that they may neutralize PAMPs thus limiting the production of proinflammatory cytokines (IL-1B, TNFa or IL-6) with direct beneficial effects on dysregulated sterile and non sterile inflammatory conditions. ? ? ?
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