Transcriptomic Analysis of Liver Indicates Novel Vaccine to Porcine Reproductive and Respiratory Virus Promotes Homeostasis in T-Cell and Inflammatory Immune Responses Compared to a Commercial Vaccine in Pigs

Abstract

One of the largest impediments for commercial swine production is the presence of Porcine Reproductive and Respiratory Syndrome Virus (PRRSV), a devastating RNA viral infection that is responsible for over $1 billion in loss in the U.S. annually. The challenge with combating PRRSV is a combination of the effect of an extraordinary rate of mutation, the ability to infect macrophages, and subversion of host immune response through a series of actions leading to both immunomodulation and immune evasion. Currently there are a handful of commercial vaccines on the market that have been shown to be effective against homologous infections, but struggle against heterologous or mixed strain infections. However, vaccination is the current best strategy for combating PRRSV, making research into new vaccine technology key. To address these issues with PRRSV and host antiviral functions a novel modified-live vaccine (MLV) able to stimulate known antiviral interferons was created and examined for its ability to potentiate effective immunity and better protection. Here, we examine gene expression in the liver of pigs vaccinated with our novel vaccine, given the liver's large role in antiviral responses and vaccine metabolism. Our study indicated that pigs administered the novel vaccine experience homeostatic gene expression consistent with less inflammation and T-cell depletion risk than pigs administered the commercial vaccine.

Current Status of Vaccines for Porcine Reproductive and Respiratory Syndrome: Interferon Response, Immunological Overview, and Future Prospects

“…Our recent research used an infectious DNA clone of the PRRSV-P129 for virus replication-competent expression of a cohort of optimized subtypes of porcine IFNs based on a functional characterization of their antiviral responses. As expected, these MLV-129p-IFN constructs induced comparable or better protection compared with a commercial vaccine in grower pigs regarding the body temperature, lung lesion score, and virus titer, as seen in [82,83] (and unpublished data). Furthermore, these studies also profiled signature gene-responsive pathways using transcriptomic analyses in the livers of pigs vaccinated with MLV-129p-IFNmix to reveal an obtained IFN response mediated by the virus replication-competent expression of IFNs in vivo [82].…”

“…As expected, these MLV-129p-IFN constructs induced comparable or better protection compared with a commercial vaccine in grower pigs regarding the body temperature, lung lesion score, and virus titer, as seen in [82,83] (and unpublished data). Furthermore, these studies also profiled signature gene-responsive pathways using transcriptomic analyses in the livers of pigs vaccinated with MLV-129p-IFNmix to reveal an obtained IFN response mediated by the virus replication-competent expression of IFNs in vivo [82]. Consistent with the multifunctional role of IFNs, we detected 197 significantly differentially expressed genes (DEGs) that were enriched in pathways of inflammation and stress responses, in addition to those spanning both innate and humoral immune responses.…”

“…In contrast to the upregulation of common ISGs, we also observed a downregulation of interleukin 2 (IL-2) and LAG3 inhibitory signaling, which functions in maintaining T-cell proliferation and activation. These findings suggest that introducing unconventional IFNs in PRRSV MLV vaccines may stimulate the interferon response in a timely manner and lead to better protection in the tested period [ 82 ]. We also performed a comparative transcriptomic study regarding small-RNA composition and differential micro-RNA responses to PRRSV infection and treatments with different subtypes of type I IFNs, particularly the IFN-α and IFN-ω subtypes, in porcine alveolar macrophages (PAMs).…”

“…Another kind of study highlighted the remarkable antiviral properties of IFNs, underscoring their potential to amplify immune responses in pigs and provide a crucial layer of protection [ 84 ]. Through meticulous in vitro and liver organ studies, researchers discovered that the IFN-α, IFN-β, and IFN-ω subtypes offer robust immunity and superior protection at the molecular level [ 82 , 83 ]. This leads to reduced viral-induced stress on organs and the immune system.…”

“…Additionally, a notable under-expression of genes associated with acute inflammatory responses was observed. These findings suggest that employing IFN as a co-expressed adjuvant could be a strategic means to counteract PRRSV’s immune suppression and maintain optimal cellular homeostasis [ 67 , 82 , 83 , 185 ].…”