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. the mannan-binding protein and mannose-binding lectin) may be considered as an ante-antibody . The role for the mannose-binding protein as an antecedent of antibodies is based on convincing in vitro evidence 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 the mannose-binding protein in host defense. We have generated MBP-A null mice that will allow a determination of whether an absolute or relative lack of the mannose-binding protein predisposes to infection. We plan to generate double knockout mice which will allow us to determine the relative roles of the mannose-binding protein, complement and natural antibodies in first line host defense. We also plan to define the structural basis by which the mannose-binding protein multimers bind ligands. It is anticipated that these structural studies will provide important new information as to how the mannose-binding protein 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 the mannose-binding protein particularly in children below the age of two predisposes them to recurrent infections. The availability of recombinant mannose-binding protein will provide immediate opportunities for replacement therapy in selected individuals in a manner analogous to the use of gammaglobulin replacement in hypogammaglobulinemia.
