Generating Innate Immune Diversity to Recognize Newly Emerging Pathogens

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. Overview: Emergence of new and drug-resistant pathogens is a reality. Most of these pathogens contain thick carbohydrate coats that are rarely recognized by our classical antibodies (e.g., IgG). However, innate immune collectins are anti-carbohydrate antibody-like molecules, and readily recognize a range of microbes. We will determine whether tissue inflammation induces mutation in collectins such as lung surfactant proteins A and D (SP-A, SP-D), so that the mutant proteins can recognize and neutralize newly emerging pathogens. This mechanism could give an evolutionary advantage to the host animals and humans. Objectives: The objective of this project is to determine whether infection and inflammation generate a repertoire of "anti-carbohydrate antibodies" from innate immune collectin genes. Collectins or collagenous lectins have fibrillar collagen-like regions and globular carbohydrate-recognition domains (CRDs or lectin domains). These collectins bind carbohydrate moieties present on microbial surfaces and neutralize their infectivity. However, collectins are encoded by single copy genes, and do not undergo gene rearrangements or somatic mutations. Therefore, unlike antibodies, these genes do not have the classical ability to generate variant collectins. We will determine whether deamination of specific bases of mRNA results in the generation of point mutations in collectins during inflammation. New knowledge & potential outcome: Findings from this basic science study could represent a paradigm shift in the field of immunology. Our work will show whether the innate immune system instantly changes collectins SP-A and SP-D so that the mutant proteins can recognize newly emerging pathogens and prevent infectious diseases such as pneumonia (e.g., bacteria, virus, fungi). This mechanism could help to stop the emergence of new strains of influenza flu and multi-drug resistant pathogens. Our data will show whether the inflammation is a "necessary evil" during the fight against the newly emerging microbial pathogens, and that suppressing inflammation would weaken the ability of the host to fight against dangerous pathogens.