Porcine reproductive and respiratory syndrome virus activates the pentose phosphate pathway via the ROS/HIF-1α/G6PD axis to promote viral replication

  • Virulence. 2025 Dec;16(1):2585639. doi: 10.1080/21505594.2025.2585639.
Ying-Xian Ma  1  2  3 ,  Jia-Ming Yang  4 ,  Hang-Tian Mei  1  2  3 ,  Lei Zeng  1  2  3 ,  Guo-Yu Yang  2  3 ,  Jiang Wang  1  2  3  5 ,  Sheng-Li Ming  1  2  3 ,  Bei-Bei Chu  1  2  3  5  6  7
Affiliations
  • 1. College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, Henan, China.
  • 2. Key Laboratory of Animal Biochemistry and Nutrition, Ministry of Agriculture and Rural Affairs, Zhengzhou, Henan, China.
  • 3. Key Laboratory of Veterinary Biotechnology of Henan Province, Henan Agricultural University, Zhengzhou, Henan, China.
  • 4. State Key Laboratory of Membrane Biology, School of Pharmaceutical Sciences, Tsinghua University, Beijing, China.
  • 5. Key Laboratory for Animal Pathogens and Biosafety, Ministry of Education, Zhengzhou, Henan, China.
  • 6. Longhu Advanced Immunization Laboratory, Henan agricultural University, Zhengzhou, Henan, China.
  • 7. International Joint Research Center of National Animal Immunology, Henan Agricultural University, Zhengzhou, Henan, China.
PMID: 41204699 DOI: 10.1080/21505594.2025.2585639
Abstract

Porcine reproductive and respiratory syndrome virus (PRRSV), a highly contagious pathogen in swine, poses significant economic challenges to global pork production. This study elucidated the regulatory interplay between PRRSV Infection and the pentose phosphate pathway (PPP), a critical metabolic axis for anabolism. Comparative metabolomic profiling of porcine alveolar macrophages (PAMs) pre- and post-PRRSV Infection demonstrated marked upregulation of PPP activity, concomitant with elevated levels of nucleotide biosynthesis. This metabolic shift was driven by PRRSV-induced upregulation of glucose-6-phosphate dehydrogenase (G6PD), the PPP's rate-limiting enzyme. Mechanistic investigations revealed that PRRSV Infection stimulated hypoxia-inducible factor 1α (HIF-1α) expression, which transcriptionally activates G6PD. Genetic silencing of HIF-1α abolished PRRSV-mediated G6PD induction. Furthermore, Reactive Oxygen Species (ROS) accumulation was identified as the upstream regulator of HIF-1α activation during PRRSV Infection. Pharmacological ROS scavenging disrupted the ROS/HIF-1α/G6PD signaling cascade, diminished NADPH and reduced glutathione production, and consequently attenuated viral proliferation. These results established that PRRSV exploited the ROS/HIF-1α axis to reprogram host glucose metabolism through PPP potentiation, creating a biosynthetic environment conducive to viral propagation.

Keywords
G6PD; HIF-1α; PPP; PRRSV; ROS.
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