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Novel Insights into Porcine Reproductive and Respiratory Syndrome Virus Host-Pathogen Interactions
Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most significant swine viral pathogens worldwide. The lack of effective and broadly protective vaccines against PRRSV jeopardizes the success of current PRRSV control and eradication strategies. Major hurdles for PRRSV vaccine development are high genetic and antigenic heterogeneity, and an incomplete understanding of PRRSV biology; including viral determinants of cell entry, virus immune escape mechanisms, and ability of PRRSV to persist in the host. This dissertation explores some key molecular mechanisms involved in the host-PRRSV interactions. Here, I demonstrate that PRRSV infection in pigs modulates the host transcriptional responses during the acute and persistent stages of infection. In acute infection, PRRSV-infected alveolar macrophages (PAMs) exhibit upregulated expression of NF-κB signaling inhibitors NFKBIA, NFKBID, NFKBIZ, TNFAIP3 and T-cell exhaustion markers. In contrast, during persistent infection, virus infection suppresses genes involved in apoptosis and trafficking of antigen specific T-cells. This results in decreased recruitment of PRRSV-specific T-cells at the site of persistence and a delay of infected cell clearance. These studies also provide knowledge on the mechanisms that PRRSV employs to escape host immune responses. Additionally, I show that the cDNA form of PRRSV 5’ untranslated region and transcription regulatory sequences contains previously unidentified cryptic eukaryotic promoter activity and can induce the expression of a luciferase reporter gene. In this dissertation, I have also described a critical discovery associated with PRRSV cellular tropism. One of the MARC-145 adapted PRRSV strain plaque-clones severely lost infectivity for PAMs. By performing whole-genome sequencing, one unique amino acid substitution from lysine (K) to isoleucine (I) was identified at position 160 in viral GP2. By reverse genetic approach, it was confirmed that this unique genomic change is responsible for impaired infectivity. The importance of K160 was confirmed by introducing the same mutation into another virulent PRRSV strain, which resulted into impaired infectivity in PAMs and virus attenuation in pigs. The results obtained in this dissertation collectively provide novel insights into the PRRSV host-pathogen interactions.
Chaudhari, Jayeshbhai, "Novel Insights into Porcine Reproductive and Respiratory Syndrome Virus Host-Pathogen Interactions" (2022). ETD collection for University of Nebraska - Lincoln. AAI29320757.