Project Number: 3625-32000-088-00
Project Type: Appropriated

Start Date: Mar 20, 2007
End Date: Feb 28, 2012

Objective:
Obj. 1: Identify mechanisms of PRRS virus (PRRSV) pathogenesis to develop vaccination strategies to enhance or improve immunity against PRRSV. Obj. 2: Identify mechanisms of SI virus (SIV) pathogenesis and develop vaccination strategies to enhance or provide broad cross-protection for circulating subtypes of SIV. Obj. 3: Identify the host-pathogen interactions and environmental factors that lead to PCVAD and discover effective measures to prevent, control, and eliminate this emerging disease from U.S. swine herds. Obj. 4: Develop methods of modulation of innate and adaptive immune responses to swine viral pathogens with an emphasis on modulating the effects of innate immunity on pathogenesis of viral diseases.

Approach:
For improved PRRSV control, one approach will identify strategies for improved immunoprophylaxis by testing vaccine strategies with recombinant adenoviruses expressing selected PRRS viral gene constructs to increase safety and efficacy of PRRS vaccines. For improved SIV control, one approach will identify mechanisms of SIV pathogenesis and develop vaccination strategies to enhance cross-protection for circulating subtypes of SIV. We will investigate the role of avian polymerase genes in adaptation of novel reassortant SIVs to pigs. We will study specific regions within identified genes that confer growth advantages. Another approach will maintain a contemporary repository for emerging SIV subtypes and genotypes and combine with novel vaccine approaches for improved SIV vaccines. Vaccine strategies will be developed that have broader subtype coverage through by use of better cross-reacting isolates, novel combinations of adjuvants and/or cytokines and different routes of vaccination. Specific aims are: A) Genetic, antigenic and pathogenic characterization of novel isolates; B) Evaluation of new inactivated vaccines against current isolates; and C) Evaluation of genetically engineered, modified-live vaccines against current isolates. For improved control of PCV type 2, we will conduct research to identify mechanisms of PCV type 2 (PCV2) pathogenesis in PMWS and perform genetic analysis of the replication and virulence mechanisms of PCV2 to develop vaccination strategies against porcine circoviruses. The goal is to develop recombinant virus vaccines against PMWS by attenuation of the viral replication and virulence mechanisms. In addition we will develop and evaluate multiplex diagnostic assays to detect pathogens involved in PCVAD, determine the role of endemic and novel swine viruses in inducing PCVAD, and finally evaluate genetic and biological determinants that lead to PCVAD. Our approach to develop methods for modulation of innate and adaptive immune responses to swine viral pathogens will focus on modulating the effects of innate immunity on pathogenesis of viral diseases. We will evaluate whether the early serum IFN-gamma response is caused by the interaction of PRRSV structural proteins with components of the hosts' immune system. Another approach will be to ameliorate clinical disease through prophylactic or metaphylactic administration of granulocyte-colony stimulating factor in an attempt to reduce the severity or duration of viral pneumonia associated with PRRSV and SIV. Another approach will be to investigate the B cell response to these swine viruses with a focus on immunoglobulin class switch recombination and diversification of the VDJ repertoire. These changes in B cells correlate with the appearance of neutralizing antibody, understanding the virulence mechanisms contributing to the delayed development of neutralizing antibody against PRRSV may provide essential insights into the improved control of PRRSV shedding in vaccinated and infected pigs. BSL-2: Recert 10/17/07 #0243, #0244, #0255; 6/08/07 #0268; 7/28/07 #0273; 8/27/07 #0274; 3/13/07 #0279A. BSL-Exempt; Recert 10/17/07, #0254.