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

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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.