Generating Innate Immune Diversity to Recognize Newly Emerging Pathogens

。概述：新的和抗药性病原体的出现是现实。这些病原体大多含有厚厚的碳水化合物外壳，很少被我们的经典抗体(如免疫球蛋白)识别。然而，天然免疫集合素是抗碳水化合物抗体样分子，很容易识别一系列微生物。我们将确定组织炎症是否会导致肺表面活性蛋白A和D(SP-A，SP-D)等集合素的突变，从而使突变的蛋白能够识别和中和新出现的病原体。这种机制可能会给宿主动物和人类带来进化优势。 目的：本项目的目的是确定感染和炎症是否会从先天免疫凝集素基因产生一系列的“抗碳水化合物抗体”。胶原凝集素或胶原凝集素具有纤维状的胶原样区域和球状的碳水化合物识别结构域(CRD或凝集素结构域)。这些集合素结合存在于微生物表面的碳水化合物部分，并中和它们的传染性。然而，胶原素是由单拷贝基因编码的，不经历基因重排或体细胞突变。因此，与抗体不同的是，这些基因不具有产生变异集合素的经典能力。我们将确定在炎症过程中，mRNA的特定碱基的脱氨基是否会导致集合素的点突变的产生。 新知识和潜在结果：这项基础科学研究的发现可能代表着免疫学领域的范式转变。我们的工作将表明，先天免疫系统是否会立即改变集合素SP-A和SP-D，以便突变蛋白能够识别新出现的病原体，并预防肺炎等传染病(例如细菌、病毒、真菌)。这一机制可能有助于阻止新的流感病毒株和多药耐药病原体的出现。我们的数据将表明，在对抗新出现的微生物病原体的过程中，炎症是否是一种“必要的邪恶”，而抑制炎症将削弱宿主对抗危险病原体的能力。

. 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.