Location: Virus and Prion ResearchTitle: Biotherapeutics as alternatives to antibiotics: effects of adenoviral delivered IFN-alpha and G-CSF on innate and adaptive immunity in swine Author
Submitted to: American Association of Swine Veterinarians Annual Meeting
Publication Type: Proceedings
Publication Acceptance Date: 12/1/2015
Publication Date: N/A
Technical Abstract: Acceptable alternatives to the use of antibiotics in swine practice need to be explored. The use of immunomodulators is a promising area for therapeutic, prophylactic, and metaphylactic use to prevent and combat infectious disease during periods of peak disease incidence. We developed a method to circumvent the need for production of a recombinant cytokine by using a replication-defective adenovirus vector to express cytokines of interest, including interferon-alpha (IFN-alpha) or porcine granulocyte colony-stimulating factor (G-CSF). Type I interferons, such as IFN-alpha, contribute to innate antiviral immunity by promoting production of antiviral mediators and also play a role in the adaptive immune response. G-CSF enhances neutrophil production and release from the bone marrow and is already licensed for use in humans for treatment of neutropenia and prevention of infections in those with compromised immunity. Porcine reproductive and respiratory syndrome (PRRS) is one of the most devastating and costly diseases to the swine industry world-wide and has been shown to induce a meager IFN-alpha response. Pigs administered the vector expressing porcine IFN-alpha and challenged with a moderately virulent PRRSV had lower febrile responses and decreased percentage of lung involvement. Viremia was delayed and there was a decrease in viral load in the sera of pigs. In addition, there was an increase in the number of virus-specific IFN-gamma secreting cells, as well as an altered cytokine profile in the lung 14 days post-infection, indicating that the presence of IFN-alpha at the time of infection can alter innate and adaptive immune responses to PRRSV. We further explored the use of IFN- alpha as an adjuvant given with attenuated PRRSV virus vaccine and found that it was able to totally abolish replication of the vaccine virus. Current studies are examining its use as a metaphylactic treatment for an outbreak of PRRSV to both treat and prevent spread of the virus. Initial results have been positive in that treatment of IFN- alpha mitigated the disease in pigs already infected with PRRSV and limited the spread of the virus to naïve pen mates. Intramuscular administration of the vector expressing porcine G-CSF was found to elicit a sustained neutrophilia, lasting nearly 3 weeks. In a pilot study using G-CSF with a Streptococcus suis challenge, only 25% of the pigs given G-CSF developed disease, while 75% of the non-treated pigs developed Streptococcal disease. Thus, it is possible to deliver G-CSF to pigs for a sustained increase in circulating neutrophil numbers in pigs, which may be a useful alternative to antibiotics for prevention of infectious disease, especially during times of stress and pathogen exposure such as post-weaning and post-partum.