Enhanced Resistance to Bacterial Infection in Protegrin-1 Transgenic Mice

Abstract

Antibiotic-resistant bacteria have become a public health concern. It was suggested that one source of resistant pathogens may be food-producing animals. Alternative approaches are therefore needed to enhance the resistance of farm animals to bacterial infection. Protegrin-1 (PG-1) is a neutrophil-derived antimicrobial peptide that possesses activity against a wide range of bacteria and enveloped viruses. Here we report on the production of transgenic mice that ectopically expressed PG-1 and compare their susceptibilities to Actinobacillus suis infection with those of their wild-type (WT) littermates. Of the 126 mice that were challenged with A. suis, 87% of the transgenic mice survived, whereas 31% of their WT littermates survived. The PG-1 transgenic mice had significantly lower bacterial loads in their lungs and reduced numbers of pulmonary pathological lesions. The antimicrobial function of PG-1 was confirmed in vitro by using fibroblast cells isolated from the transgenic mice but not the WT mice. Moreover, differential blood cell counts in bronchoalveolar lavage fluid indicated greater number of neutrophils in PG-1 transgenic mice than in their WT littermates after bacterial challenge. Our data suggest that the ectopic expression of PG-1 in mice confers enhanced resistance to bacterial infection, laying the foundation for the development of livestock with improved resistance to infection.

Overexpression of Porcine Beta-Defensin 2 Enhances Resistance to Actinobacillus pleuropneumoniae Infection in Pigs

“…The TG pigs showed significantly lower bacterial burden in the lungs compared to that of the WT pigs. This finding is similar to those of previous reports, which demonstrated that the expression of an additional antimicrobial peptide can enhance the killing rate of bacteria in mice (4,5). Study 2 was designed to investigate whether the results obtained in study 1 showing reduced bacterial burden in the TG-challenged lungs minimized susceptibility to infection via contact exposure to infected pigs, which was more similar to the natural infection of this disease.…”

“…Expression of an additional porcine cathelicidin peptide, PR-39, in mice showed increased resistance to group A Streptococcus infection (4). Furthermore, enhanced resistance to Actinobacillus suis infection was observed in proptegrin-1 TG mice (5). These studies demonstrate that AMPs potentially can lead to the development of infection-resistant animals, at least in TG mouse models.…”

“…Several studies have demonstrated that increased defensin expression in mice can increase resistance to bacterial infections (4,5,19). PBD-2 possesses high antimicrobial activities against a broad range of microorganisms.…”

Bacteria-induced expression of the pig-derived protegrin-1 transgene specifically in the respiratory tract of mice enhances resistance to airway bacterial infection

“…In comparison with their WT littermates, they exhibited enhanced resistance to APP bacterial infection as evidenced by their higher survival rate, lower tissue bacterial load, and milder histological severity after APP inoculation. These results were similar to those reported in the transgenic mice that exhibited ubiquitous expression of PG-1 under the control of a CMV promoter [20]. Yet, with the transgenic mice generated in the present study the likelihood of inducing bacterial resistance to antibiotics is further reduced as PG-1 expression is restricted to the respiratory tract only upon induction by bacterial infection.…”

“…In an attempt to develop new strategies for reducing antibiotic consumption in farm animal production, PG-1 was introduced as a transgene into the genome of mice which resulted in a significantly enhanced ability of these mice to fight against bacterial infections [20]. However, as the PG-1 transgene in these transgenic mice was driven by a constitutive promoter, resulting in the constant and ubiquitous expression of PG-1, development of microbial resistance would be very likely.…”