STRUCTURE-FUNCTION STUDIES ON VIRAL-HOST INTERACTIONS KEY TO ANIMAL IMMUNITY

The main goal of this research is to provide detailed molecular basis by which a number of important viral and host proteins function, and to provide important clues on how to design novel anti-viral regents key to the immunity of livestock animals. The outcome will be helpful for development of treatments and preventions against a number of infectious diseases that target livestock animals and are economically devastating. Infectious animal diseases are destructing the health of livestock and agricultural economy. Porcine reproductive and respiratory syndrome (PRRS) is a major swine disease that costs swine producers in the United States approximately $700 million annually(Neumann, Kliebenstein et al., 2005). PRRS virus (PRRSV)-infected pigs are susceptible to pneumonia and reproductive losses (Cho & Dee, 2006, Lowe, Husmann et al., 2005). Pseudorabies virus (PrV) causes fatal swine disease that is characterized by neurological symptoms and death in young piglets, and respiratory and reproductive disorders in older pigs. The acute phase of the infection with a high abortion rate and neonatal mortality causes significant economic losses(Hahn, Fadl-Alla et al., 2010, Kluge, Beran et al., 1999). Foot-and-mouth disease virus (FMDV) causes a highly contagious disease in cloven-hoofed animals, which is highly infectious and a major plague of animal farming. Although immunization of animals with vaccines that are conventionally attenuated viruses helps provide some protections, there are still disadvantages such as the risk of reversion to virulence (Vilnis, Sussman et al., 1998, Zuckermann, 2000) and the risk of interference with efficient antigen presentation (Zuckermann, 2000). Attempts to enhance the immunogenicity of vaccines have been actively sought, among which administration of immunomodulatory molecules such as cytokine IL-18 has been of considerable interests. IL-18 is a potent interferon gamma (IFN-g) inducing factor, which plays a central regulatory role in host immune response to viral and microbial infections(Vivier, Tomasello et al., 2008). It was also shown that IL-18 may be useful as a therapeutic agent for the enhancement of immune responses and as a vaccine adjuvant, especially in neonatal piglets(Muneta, Goji et al., 2002). In fact, treatment of animals with exogenous IL-18 was reported to confer protections against viral infections, such as PRRSV(Shen, Jin et al., 2007), PrV(Kim, Kim et al.) and FMDV(Shi, Wang et al., 2007). It was also shown that IL-18 may be useful as a therapeutic agent for the enhancement of immune responses and as a vaccine adjuvant, especially in neonatal piglets(Muneta et al., 2002). Poxviruses including swinepox virus (Afonso, Tulman et al., 2002) adopt unique host immune evasion mechanisms, one of which is inhibiting IL-18 singling by viral protein IL-18BPs. In addition, two intracellular inhibitors of type I IFN antiviral activities, K1 and C7 from vaccinia virus (VACV), were discovered (Meng, Jiang et al., 2009, Meng, Schoggins et al., 2012). Further more, poxviruses use a unique yet unclear mechanism for membrane biogenesis, including key proteins A6 and H7. Knocking out A6 or H7 will be lethal for viral replication in mammalian cells. Revealing the mechanism by which these host range proteins target and inhibit animal host immunity proteins will provide key information on further development of anti-viral drugs. Finally, an essential host molecular chaperone, Hsp90, is nearly universally required for viral replication (reviewed in (Geller, Taguwa et al., 2012)) and development of cancer. Therefore, inhibiting Hsp90 by novel inhibitors will present an important way to fight viral infection and cancer.