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

宿主防御肽在生产动物肠道疾病病理生理学中的作用

• 批准号: RGPIN-2017-04832
• 负责人: Cobo, Eduardo
• 金额: $ 4.37万
• 依托单位: University of Calgary
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=766022
• 关键词: Function; host; defense; peptides; pathophysiology

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.

大肠杆菌病由致病性大肠杆菌和沙门氏菌引起的肠道炎症是仔猪和小牛中常见的破坏性疾病（传染性结肠炎），引起肠道破坏性病变，导致疼痛、腹泻和死亡。这种疾病严重影响加拿大牲畜的可持续性，因为生产力下降（体重增加不佳，死亡率增加，治疗费用增加）和动物福利问题。此外，由于大肠杆菌的日益流行，目前使用常规抗生素的治疗越来越受到政府当局、零售商和消费者的严格审查。生产动物中的大肠杆菌和沙门氏菌分离株对抗生素耐药。这些多重耐药细菌可能会导致动物和人类的疾病，而这些疾病是无法治疗的。同样令人关切的是，供人类消费的产品中可能存在的抗生素残留量。本研究计划将研究生产动物肠道内的先天免疫防御，主要由宿主防御肽（包括嗜中性粒细胞和肠道细胞大量分泌的cathelicidins）贡献。特别感兴趣的是确定cathelicidins在感染性结肠炎发病机制中的功能及其对肠道宿主微生物防御的贡献。我们的方法结合了体外实验与培养的肠上皮细胞和体内模型的感染性结肠炎的小鼠剥夺cathelicidins。具体的目的是确定cathelicidins如何促进白细胞快速迁移到肠道，有助于病原体消除。此外，为了确定是否cathelicidins增强肠中的粘蛋白屏障和上皮完整性。这些作用一起可以快速恢复肠道内稳态，避免与肠道中病原体持续存在相关的炎症损伤。将进一步研究这些原理，以确定凯萨林菌素（天然或外源性）是否可缓解靶动物种属（猪）的感染性结肠炎。该计划探讨了生产动物肠道中的先天防御，特别是cathelicidins在病原体清除和结肠炎解决中的作用和机制。该信息高度适用于开发cathelicidins（单独或与减少剂量的抗生素组合）作为生产动物的抗菌和免疫调节治疗剂。这种传染病控制战略对加拿大农业非常有益，因为由于出现了抗菌素耐药性和食物链中存在药物残留，在食用动物中使用常规抗生素变得不可持续。