Innate immunomodulatory strategies and pathogenic basis for nidoviruses

Virus-host interactions play a critical role in determining the outcome of viral infections, including clearance, persistence, or disease development. In response to viral invasion, the host deploys innate and adaptive immune responses. Nidoviruses such as SARS-CoV-2 and porcine reproductive and respiratory syndrome virus (PRRSV) trigger the activation of the NF-κB pathway and induce the production of inflammatory cytokines. Elevated levels of proinflammatory cytokines contribute to the severity of COVID-19, leading to acute respiratory distress syndrome and increased mortality. The current study identifies specific proteins of SARS-CoV-2, namely ORF3a, M, ORF7a, and N, as activators of the NF-κB pathway. Particularly, the ORF7a protein induces the expression of various proinflammatory cytokines and chemokines commonly elevated in severe COVID-19 patients. Targeting the ORF7a protein may present a potential strategy to mitigate the excessive inflammation in COVID-19. Interferons (IFNs) play a crucial role in the host's defense against viral infections. However, PRRSV, a swine arterivirus, has evolved to equip the mechanisms to inhibit IFN production and signaling. My study investigates the molecular mechanism by which PRRSV downregulates the PML protein, an IFN stimulation gene and a negative regulator of viral replication. PRRSV- infected cells exhibit a significant reduction in PML nuclear bodies, indicating the involvement of PRRSV nsp1β in PML downregulation. Gene silencing experiments confirm that PML inhibits PRRSV replication. Coexpression of PML isoforms suppresses viral replication, and PML-II and PML-IV are the strongest antiviral proteins. The PML downregulation occurs through the ubiquitination-dependent proteasomal degradation pathway. The interaction between PRRSV nsp1β and PML is common among representative viruses in the Arteriviridae family. Mutational analysis reveals that specific mutations in PRRSV nsp1β disrupt its binding to PML, preventing PML degradation. These findings uncover a novel strategy employed by arteriviruses to enhance viral replication through targeted degradation of PML. Co-infection of PRRSV with a secondary bacterial pathogen exacerbate proinflammatory cytokine production and contribute to the development of porcine respiratory disease complex (PRDC). A double-mutant PRRSV containing the mutation in the nsp1β and N genes has been generated. In cells, the mutant PRRSV restored IFN-β expression and exhibited decreased production of NF-κB-dependent inflammatory cytokines compared to the wild-type virus when co-infected with Streptococcus suis. In pigs, double-mutation PRRSV showed clinical attenuation and reduced expression of proinflammatory cytokines and chemokines. These results indicates that genetic modifications targeting IFN suppression and NF-κB activation functions of PRRSV holds a promise in developing a new class of vaccines to mitigate the severity of PRRS and PRDC during bacterial co-infection.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

VMS - Pathobiology

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2023

Author dc:creator

• Su, Chia-Ming

Contributors dc:contributor

• Yoo, Dongwan
• Jarosinski, Keith
• Wang, Leyi
• Zuckermann, Federico

• Nidovirus
• Sars-cov-2
• Porcine Reproductive And Respiratory Syndrome Virus
• Prrsv
• Interferons
• Nf-κb
• Cytokines
• Promyelocytic Leukemia Protein
• Pml

Statement dc:rights

• Copyright 2023 Chia-Ming Su

Language dc:language

en, eng

Handle dc:identifier

https://hdl.handle.net/2142/121354

OAI record oai:identifier

https://www.ideals.illinois.edu/oai-pmh?verb=GetRecord&metadataPrefix=etdms&identifier=oai%3Awww.ideals.illinois.edu%3A2142%2F121354