#07-201

Complete

Date Full Report Received

07/29/2009

Date Abstract Report Received

07/29/2009

Investigation

Institution:
Primary Investigator:

Porcine multisystemic wasting syndrome (PMWS) emerged in the mid and late 1990s in herds infected with porcine circovirus type-2 (PCV-2). A growing database of field observations and experimental animal infections considers PCV-2 to be either the cause of PMWS or to acts in concert with other factors to cause disease (Allen & Ellis, 2000). PMWS is responsible for significant economic losses in the US as well as around the world (Merial, 2004). There are no specific treatments for the disease although several vaccines have appeared. The complexity of PMWS may be related to the immunoregulatory properties of the virus. In an effort to address the immunological aspects of PCV-2 induced PMWS that might determine future vaccine strategies, we undertook a comparative study using 64 isolator piglets infected with either PCV-2, PRRSV or swine influenza (SIV); all are respiratory pathogens and the preliminary studies that were confirmed in this study indicated that germfree isolator piglets could resolve SIV infections in ~21 days. Therefore we wanted to identify parameters of immunity that correlated with this successful outcome while identifying immunological features that might explain why PCV-2 and PRRSV infected piglets were unable to clear the infection. It was thought that the optimal vaccine for both of these persistent infections should be designed to overcome the weaknesses in the immune response when compared to SIV.

This “3-virus” comparative study clearly showed that neither PRRSV nor PCV-2 infected piglets generated activated cytotoxic or helper T cells at the site of infection during the course of the study. The former cell type destroys virus-infected cells while the latter cell types stimulate the production of viral neutralizing (VN) antibodies. PCV-2, piglets did respond with normal production of immunoglobulins which argues against a direct inhibitor of overall B cell development. However and unlike SIV-infected piglets, PCV-2 infections did not promote antibody responses to irrelevant antigens (used as a test of function of the antibody system) and showed depressed development of helper T cells. Therefore our studies confirmed some aspects of the “immune suppressive” theory relating to PCV-2. However we were unable to pinpoint the cause of the depressed antibody response. Since PCV-2 infected piglets were unable to “mature their immune system” and to make robust antibody responses, we hypothesize that PCV-2 lacks the adjuvant effect of SIV and that future vaccine strategies should focus on resolving this apparent problem since the virus does not appear to cause any obvious immune dysregulation. One approach is to use polyvalent vaccines, perhaps including SIV or bacterial adjuvants, such as probiotics, to simultaneously stimulate the development of cytotoxic T cells and activated helper T cells. The major feature of PRRSV infection was the extreme polyclonal and non-specific B cells activation that drove B cells to end-stage plasma cells while simultaneously depleting the population of activated B cells that could potentially respond to the virus. Perhaps a feedback loop from these cells also inhibited development of cytotoxic T cells. It seems that PRRSV vaccine development should focus on recombinant and modified vaccines that reduce B cell immune dysregulation while still promoting an immune response. We believe the isolator piglet model can serve as an important test bed in developing and improving vaccines for PCV-2 because: (1) animals are especially sensitive to pathogens and (2) all piglets start with the same environmental background (unlike conventional piglets).