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Peer-reviewedCC BY-NC-ND 4.0Virologica Sinica

A HiBiT-Tagged influenza A virus reporter system reveals cytokine-inhibitory micropeptide 53 as a modulator of viral infection and immunopathology

  • Shujie Ma1,2,3
  • Sha Liu1,2,3
  • Conghui Zhao1,2,3
  • Wenjun Shi4
  • Chunping Zhang1,2,3
  • Jiacheng Huang1,2,3
  • Yang Wang1,2,3
  • Xiaoxuan Zhang1,2,3
  • Haoxi Qiang1,2,3
  • Huanhuan Wang1,2,3
  • Peilin Li1,2,3
  • Xinhui Chen1,2,3
1 more authors
  • Ziyi Zhang1,2,3
4 affiliations
  1. 1Joint Laboratory of Animal Pathogen Prevention and Control of Fujian-Nepal, College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China
  2. 2Key Laboratory of Animal Pathogen Infection and Immunology of Fujian Province, College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China
  3. 3Key Laboratory of Fujian-Taiwan Animal Pathogen Biology, College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China
  4. 4Animal Quarantine Laboratory, Technology Center of Qingdao Customs, Qingdao 266000, China
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Abstract

Influenza A virus (IAV) remains a major threat to human and animal health, highlighting the need for efficient approaches to identify host factors and antivirals. Reporter viruses are critical tools for these efforts, but incorporating large reporter genes often compromises viral fitness and genetic stability. Here, we developed a replication competent reporter IAV by fusing an 11-amino acid HiBiT tag into the nonstructural protein 1 (NS1) of the A/WSN/1933 (H1N1) backbone. The modified virus retained parental virion morphology, comparable replication kinetics, and in vivo tissue tropism, while enabling the highly sensitive, rapid, and quantitative detection of viral replication. Using this reporter virus, we established a robust high-throughput screening (HTS) platform with excellent assay quality and validated its capability to identify host regulators of IAV infection. Application of this platform to host-encoded micropeptides (miPEPs) led to the identification of cytokine-inhibitory micropeptide 53 (CIM53) as a novel regulator of IAV replication. Mechanistically, CIM53 promoted IAV replication by intrinsically suppressing antiviral innate immune responses. Furthermore, although CIM53 enhanced viral replication, its immunomodulatory activity contributed to reduced lung injury and improved survival when combined with Oseltamivir (OSV) treatment in infected mice. Our study establishes a highly practical screening platform for virological research and highlights CIM53 as a potential host-directed adjunct therapy for severe IAV infection.

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Cite

BibTeXRIS
BibTeX
@article{ma2026hibittagged,
  title = {{A HiBiT-Tagged influenza A virus reporter system reveals cytokine-inhibitory micropeptide 53 as a modulator of viral infection and immunopathology}},
  author = {Shujie Ma and Sha Liu and Conghui Zhao and Wenjun Shi and Chunping Zhang and Jiacheng Huang and Yang Wang and Xiaoxuan Zhang and Haoxi Qiang and Huanhuan Wang and Peilin Li and Xinhui Chen and Ziyi Zhang},
  journal = {Virologica Sinica},
  year = {2026},
  month = sep,
  doi = {10.1016/j.virs.2026.09.003},
  url = {https://doi.org/10.1016/j.virs.2026.09.003},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - A HiBiT-Tagged influenza A virus reporter system reveals cytokine-inhibitory micropeptide 53 as a modulator of viral infection and immunopathology
AU  - Shujie Ma
AU  - Sha Liu
AU  - Conghui Zhao
AU  - Wenjun Shi
AU  - Chunping Zhang
AU  - Jiacheng Huang
AU  - Yang Wang
AU  - Xiaoxuan Zhang
AU  - Haoxi Qiang
AU  - Huanhuan Wang
AU  - Peilin Li
AU  - Xinhui Chen
AU  - Ziyi Zhang
PY  - 2026
DA  - 2026/09/05
JO  - Virologica Sinica
DO  - 10.1016/j.virs.2026.09.003
UR  - https://doi.org/10.1016/j.virs.2026.09.003
AB  - Influenza A virus (IAV) remains a major threat to human and animal health, highlighting the need for efficient approaches to identify host factors and antivirals. Reporter viruses are critical tools for these efforts, but incorporating large reporter genes often compromises viral fitness and genetic stability. Here, we developed a replication competent reporter IAV by fusing an 11-amino acid HiBiT tag into the nonstructural protein 1 (NS1) of the A/WSN/1933 (H1N1) backbone. The modified virus retained parental virion morphology, comparable replication kinetics, and in vivo tissue tropism, while enabling the highly sensitive, rapid, and quantitative detection of viral replication. Using this reporter virus, we established a robust high-throughput screening (HTS) platform with excellent assay quality and validated its capability to identify host regulators of IAV infection. Application of this platform to host-encoded micropeptides (miPEPs) led to the identification of cytokine-inhibitory micropeptide 53 (CIM53) as a novel regulator of IAV replication. Mechanistically, CIM53 promoted IAV replication by intrinsically suppressing antiviral innate immune responses. Furthermore, although CIM53 enhanced viral replication, its immunomodulatory activity contributed to reduced lung injury and improved survival when combined with Oseltamivir (OSV) treatment in infected mice. Our study establishes a highly practical screening platform for virological research and highlights CIM53 as a potential host-directed adjunct therapy for severe IAV infection.
SN  - 1674-0769
SN  - 1995-820X
ER  -