Pseudorabies virus UL13 primes inflammatory response through downregulating heat shock factor 1

Area of Science:

• Virology
• Molecular Biology
• Immunology

Background:

• Pseudorabies virus (PRV) is a significant swine pathogen causing economic losses.
• Alpha-herpesvirus infections can impact host cellular responses, including the heat shock response.
• Heat shock factor 1 (HSF1) is a key regulator of cellular stress responses.

Purpose of the Study:

• To investigate the role of PRV protein UL13 in regulating HSF1 during infection.
• To elucidate the impact of HSF1 modulation on PRV replication and host inflammatory responses.
• To explore the therapeutic potential of targeting the HSF1 pathway against alpha-herpesvirus infections.

Main Methods:

• Utilized cell culture models and knockout cell lines.
• Investigated viral protein interactions and enzymatic activities (serine/threonine protein kinase).
• Analyzed gene expression (mRNA levels) and protein phosphorylation.
• Assessed viral replication rates and inflammatory cytokine production (IL-6, TNF-α, IL-1β).
• Examined host immune signaling pathways (NF-κB, p38MAPK).

Main Results:

• PRV infection downregulates HSF1 mRNA levels.
• Viral protein UL13's kinase activity is essential for HSF1 mRNA inhibition and phosphorylation.
• UL13 increases HSF1 activity despite reducing HSF1 mRNA levels.
• HSF1 deficiency or inhibition significantly reduces PRV replication.
• HSF1 knockout accelerates NF-κB and p38MAPK activation.
• UL13 modulates cytokine production and contributes to PRV-induced pathology.

Conclusions:

• PRV UL13 utilizes its kinase activity to downregulate HSF1 mRNA, thereby promoting viral replication and inflammation.
• HSF1 plays a critical role in controlling PRV replication and influencing host immune signaling.
• Targeting the UL13-HSF1 interaction presents a potential therapeutic strategy against PRV and other alpha-herpesviruses.