Innate immunity plays a key role in the host's early surveillance against an infectious challenge. The immediate barriers to noxious stimuli take on many guises. The molecules that are involved in innate immunity in higher organisms, like mice and men, often have their origins in very primitive life forms that lack specific immunity. In this proposal, we aim to extend our investigations into one such molecule in which we have had a long-standing interest. The mannose-binding protein (a.k.a. MBP, the mannan-binding protein and mannose-binding lectin) maybe considered as an """"""""ante-antibody"""""""". The role for MBP as an antecedent of antibodies is based on convincing in vitro evidence, but circumstantial in vivo data. The proposed role for MBP is in immediate defense against an infectious agent during the lag period prior to the generation of a specific immune response. The goals of this proposal are to determine the precise in vivo role for MBP in host defense. We plan to generate animals that will allow a determination of 1) whether an absolute or relative lack of MBP predisposes to infection 2) the relative roles of MBP and complement in first line host defense 3) the relative roles of MBP and natural antibodies in innate immunity. We also plan to define the structural basis by which MBP multimers bind ligands. It is anticipated that these structural studies will provide important new information as to how MBP is able to recognize the patterns of carbohydrates that adorn the surfaces of a wide range of bacterial, fungal and viral agents, yet interact with a paucity of self glycoproteins. The studies described in this proposal, if successful will complement and add significant credence to the clinical observations that lack of MBP, particularly in children below the age of two, predisposes them to recurrent infections. The availability of recombinant MBP will provide immediate opportunities for replacement therapy in selected individuals in a manner analogous to the use of gammaglobulin replacement in hypogammaglobulinemia.
