1. Academic Validation
  2. SREBP2-dependent lipid droplet formation enhances viral replication and deteriorates lung injury in mice following IAV infection

SREBP2-dependent lipid droplet formation enhances viral replication and deteriorates lung injury in mice following IAV infection

  • Emerg Microbes Infect. 2025 Dec;14(1):2470371. doi: 10.1080/22221751.2025.2470371.
Xinsen Li 1 Lu Li 2 Jijing Tian 1 Ruijing Su 1 Jiali Sun 1 Yuli Li 1 Lige Wang 1 Hongye Zhou 1 Shuhan Sha 1 Jin Xiao 3 Hong Dong 4 Caiyun Huo 1 Yanxin Hu 1 Hanchun Yang 1
Affiliations

Affiliations

  • 1 National Key Laboratory of Veterinary Public Health and Safety, Key Laboratory of Animal Epidemiology of Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, People's Republic of China.
  • 2 Infectious Disease Department, Peking University Third Hospital, Beijing, People's Republic of China.
  • 3 Key Laboratory of Veterinary Bioproduction and Chemical Medicine of the Ministry of Agriculture, Zhongmu Institutes of China Animal Husbandry Industry Co., Ltd, Beijing, People's Republic of China.
  • 4 Beijing Key Laboratory of Traditional Chinese Veterinary Medicine, Beijing University of Agriculture, Beijing, People's Republic of China.
Abstract

Influenza A virus (IAV) is a significant zoonotic pathogen that poses a considerable challenge to public health due to its continuous mutations. Lipid droplets (LDs) have been shown to play an important role in the process of several viral infections. However, their role in IAV Infection remains unclear. Here, we found that IAV Infection altered the lipid metabolism and increased the content of LDs in the lungs of mice. In vitro, IAV Infection also mediated the formation of LDs in A549 cells. Besides, inhibition of the formation of lipid droplets can significantly suppress IAV replication and the release of inflammatory factors, indicating that LDs could facilitate the virus replication and inflammatory response. Furthermore, we discovered that IAV Infection could activate the SREBP2, a crucial lipid-regulating transcription factor that regulates the expressions of downstream proteins named HMGCR and HMGCS. HMGCR and HMGCS involved in the process of Cholesterol synthesis, which further promoted the formation of LDs. Additionally, the use of fatostatin that specifically inhibits the maturation of SREBP2 was able to significantly suppress the viral replication of H5N1 in cells and effectively ameliorated IAV-induced lung injury in mice, which eventually promoted the survival rate of infected mice. Taken together, we demonstrate the essential roles of lipid metabolism and LD formation in IAV replication and pathogenesis, which may better facilitate the advancement of new strategies against IAV Infection, especially the highly pathogenic H5N1 virus.

Keywords

Influenza A virus; SREBP2; lipid droplets; lung injury; viral replication.

Figures
Products