Function of host defense peptides in pathophysiology of intestinal diseases in production animals

致病性大肠埃希菌和沙门氏菌引起的肠炎。是一种常见的破坏性疾病(传染性结肠炎)，在仔猪和牛犊中引起肠道破坏性损害，导致疼痛、腹泻和死亡。由于生产力下降(体重增加不佳、死亡率增加、治疗费用增加)和动物福利问题，这种疾病严重影响了加拿大牲畜的可持续性。此外，目前使用常规抗生素的治疗方法越来越受到政府当局、零售商和消费者的审查，因为在对抗生素具有抗药性的生产动物中，大肠杆菌和沙门氏菌分离物的流行率越来越高。这些具有多重抗药性的细菌可能会导致动物和人患上疾病，但目前还没有治疗方法。同样令人担忧的是供人类食用的产品中可能存在的抗生素残留量。因此，有必要开发新型的食用动物抗炎抗菌剂。*本研究计划将研究生产动物肠道中的天然免疫防御，主要由宿主防御肽贡献，包括由中性粒细胞和肠道细胞大量分泌的天冬氨酸。特别感兴趣的是确定肠道毒素在感染性结肠炎发病机制中的作用以及它们对肠道宿主-微生物防御的贡献。我们的方法结合了培养的肠道上皮细胞的体外实验和在体小鼠的感染性结肠炎模型。其具体目的是确定放线菌素如何促进白细胞快速迁移到肠道，从而帮助消除病原体。此外，为了确定肠道粘蛋白屏障和肠黏膜上皮完整性是否增强。这些作用结合在一起，可以迅速恢复肠道内的动态平衡，避免与病原体在肠道中持续存在相关的炎症损害。将进一步研究这些原理，以确定放线菌素(自然发生的或外源性的)是否可以减轻目标动物物种(猪)的感染性结肠炎。*本计划探索生产动物肠道中的先天防御，特别是肠道毒素在病原体清除和结肠炎解决中的作用和机制。这些信息被高度应用于开发放线菌素(单独或与减少的抗生素剂量组合)作为生产动物的抗菌和免疫调节疗法。这种传染病控制策略对加拿大农业非常有益，因为由于出现抗菌素耐药性和食物链中存在药物残留，传统抗生素在食品类动物中的使用正变得不可持续。

Inflammation of the intestine by pathogenic Escherichia coli and Salmonella spp. is a common devastating disease (infectious colitis) in piglets and calves that provokes destructive lesions in the intestine causing pain, diarrhea and death. This illness severely impacts sustainability of Canadian livestock due to reduced productivity (poor weight gain, increased mortality, treatment costs) and animal welfare issues. In addition, current treatments using conventional antibiotics are increasingly scrutinized by governmental authorities, retailers and consumers due to the increasing prevalence of E. coli and Salmonella isolates in production animals that are resistant to antibiotics. These multi-drug resistant bacteria may cause disease in animals and people for which there is no treatment. Equally concerning are the residual amounts of antibiotics that may be present in products intended for human consumption. Therefore, there is need to develop novel anti-inflammatory antimicrobials for food animals.***This research program will investigate innate immune defenses in the intestine in production animals, mostly contributed by host defense peptides, including cathelicidins abundantly secreted by neutrophils and intestine cells. Of particular interest is to define the function of cathelicidins in the pathogenesis of infectious colitis and their contribution to intestinal host-microbial defenses. Our approach combines in vitro experiments with cultured intestinal epithelial cells and in vivo models of infectious colitis in mice deprived of cathelicidins. The specific aims are to determine how cathelicidins promote a rapid migration of leukocytes into the intestine that could aid pathogen elimination. Moreover, to determine whether cathelicidins enhance the mucin barrier and epithelial integrity in the gut. These effects together could quickly restore intestinal homeostasis avoiding the inflammatory damage associated with pathogen persistence in the intestine. These principles will be investigated further to determine if cathelicidins (either naturally occurring or exogenous) mitigate infectious colitis in the target animal species (pigs). ***This program explores innate defenses in the gut of production animals and specifically, the roles and mechanisms of cathelicidins in pathogen clearance and resolution of colitis. The information is highly applied to developing cathelicidins (either alone or in combination with reduced doses of antibiotics) as antimicrobial and immunomodulatory therapeutics in production animals. Such strategies for infectious disease control are greatly beneficial for the Canadian agriculture since the use of conventional antibiotics in food producing animals is becoming unsustainable due to the emergence of antimicrobial resistance and the presence of drug residues in the food chain.