#13-241

Complete

Date Full Report Received

07/16/2014

Date Abstract Report Received

07/16/2014

Investigation

Institution: , ,
Primary Investigator:
Co-Investigators: Federico A. Zuckermann, Fernando Osorio, Michael P. Murtaugh

PRRSV infection is a chronic infection, persisting in an animal for months. While the early stages of disease are associated with virus in the blood, that virus is eventually cleared; however, virus remains in the lymphoid tissues. This persistence is a problem because the virus can still transmit to naïve animals and cause disease. We’ve known for some time that a single animal can clear the infection, and the use of load-close-expose (LCE) protocols have been used to return herds to a PRRSV-negative status. Unfortunately, it can take more than 200 days to eliminate PRRSV from the herd. This information is useful because it tells us that the pig’s immune system can eventually clear PRRSV from the body. Thus, the immune system “see’s” the virus in the context necessary to remove free virus and kill cells infected with the virus; but, we do not completely understand why it takes so long and what immune factors are necessary for the removal of virus.

From the perspective of an immunologist trying to find solutions to combat PRRSV, there are various approaches. First, a primary approach would be the development of a vaccine that induces protective immunity prior to infection. This typically requires knowing which parts of the virus to include in the vaccine so immunity is directed against the portions of the virus that leads to blocking infection, or neutralizing. That said, for many vaccines currently used that work, this hasn’t always been determined. But, that’s because the vaccine works and therefore, there is little need to know what the immune response targets. But, this is not entirely the case for PRRSV – current vaccines do eventually provide some protection, but it’s not ideal. Thus, to find a solution for the development of an improved vaccine, the portions of the virus that a protective immune response is directed against need to be identified.

Research has shown that antibody that develops in the late stages of PRRSV infection do prevent PRRSV infection when transferred into naïve pigs that are then challenged. Identifying the regions of the virus that these antibodies bind to neutralize PRRSV infectivity will benefit further development of a vaccine. In addition to identifying regions of the virus that antibodies must target to prevent infection, it will be important to consider the cellular immune component. This arm of the immune system is required to kill cells in the body that harbor PRRSV. If the antibody component of immunity doesn’t completely block infection, and some cells are infected, immune cells will kill the infected cells. Immune cells, specifically T cells, use a variety of different mechanisms to kill PRRSV infected cells. The regions of the virus recognized by PRRSV-specific T cells and the mechanism used to kill PRRSV infected cells needs to be identified in order to know that the proper immune response has been initiated bya vaccine. This warrants the development of swine reagents necessary for identifying the T cells, but also development of assays to confirm the PRRSV-specific cells are fully functional. The development of such reagents will benefit PRRSV research, as well as other research focusing on solutions for swine diseases.

Another approach, not exclusive from that described above, is identifying mechanisms that PRRSV uses to dampen the innate immune response and/or interventions that enhance anti-PRRSV immunity. Innate immunity is responsible for turning on the portion of the immune system that makes antibodies and induces development of PRRSV-specific T cells. This area of research is extremely complex and the area we know little about. That said, it has been shown that administration the immune cytokine IFN-α at the time of infection, can significantly alter disease outcome. The cellular component of anti-PRRSV immunity was enhanced and the pig better controlled the virus. It has been shown also that PRRSV can alter the production of IFN-, so it’s likely these observations are connected. While a significant portion of research has been done on PRRSV pathogenesis, we still know little on the mechanisms PRRSV utilizes to alters the host immune system. A clearer understanding of the mechanisms used in vivo, not just in cell-culture systems, in which PRRSV alters innate immunity and/or adaptive immunity are necessary for moving forward. This approach could include supplementing with various immune factors to determine if it enhances anti-PRRSV immunity, as well as confirming what happens in cell-culture actually occurs in the pig.

The basic understanding of how PRRSV interferes with the immune system will be beneficial primarily for the development of a vaccine. It’s highly likely that a live-attenuated vaccine will be the best approach for PRRSV. Identifying regions of the virus that interfere with PRRSV-specific immunity, and using techniques to remove these portions of the virus, will lead to the development of a rationally attenuated vaccine. In addition, proteins that enhance the protective immune response could be added to the vaccine. Overall, we can use the pig’s response to natural infection to teach us which parts of the virus a vaccine should be directed against; however, mechanistic assays will need to be used to confirm the function of isolated immune components. Reserach efforts focused on the mechanism in which PRRSV alters the host immune system (such as T cell development, antigen presentation, and induction of PRRSV-specific lymphocytes) will be necessary to explain the inability of the pig to develop rapid and sterilizing immunity following infection.