Knocking down or deleting host factor S100 calcium-binding protein A4 attenuates influenza A virus replication, while overexpressing the protein enhances viral replication in human alveolar epithelial cells, according to research published in Frontiers in Microbiology. A research team from China Jiliang University, Zhejiang Sci-Tech University, and Zhejiang Difference Biotechnology Co., Ltd investigated how host factors regulate influenza A virus replication, focusing on the cellular role of S100A4 during infection in A549 cells.
The researchers manipulated S100A4 expression in A549 cells to determine its impact on viral growth. When S100A4 was knocked down using RNA interference or knocked out using CRISPR/Cas9 gene-editing technology, influenza A virus replication was attenuated. Conversely, the overexpression of S100A4 in A549 cells led to enhanced viral replication, identifying the host factor as a positive modulator of influenza A virus infection.
To understand the molecular mechanism underlying this enhancement, the team examined interactions between S100A4 and viral proteins. Co-immunoprecipitation experiments confirmed that S100A4 physically interacts with the influenza A virus M2 protein. Furthermore, confocal microscopy demonstrated that the viral M2 protein co-localizes with endogenous S100A4 inside influenza-infected A549 cells.
The researchers next mapped the specific binding domain mediating this host-pathogen interaction. Truncation analysis confirmed that amino acids 45 through 62 of the viral M2 protein constitute the main interaction region that binds to host S100A4 in the infected human alveolar epithelial cells.
Additional functional experiments revealed that S100A4 deletion impairs multiple stages of the viral cycle. Viral entry was reduced following S100A4 deletion. Furthermore, viral polymerase activity was significantly decreased in S100A4-knockout A549 cells compared to the activity measured in wild-type A549 cells, indicating that S100A4 is involved in maintaining polymerase activity.
The host factor also influenced cellular immune defenses against the pathogen. Overexpression of S100A4 resulted in the downregulation of interferon-beta, while the messenger RNA levels of the interferon-stimulated genes ISG15 and BST2 were also significantly reduced. The authors concluded that S100A4 positively modulates influenza A virus replication by participating in viral entry, polymerase activity maintenance, and innate immune regulation, pointing to an underexplored avenue for antiviral therapeutic intervention.
The investigation, published as an original research article in the Virology section of Frontiers in Microbiology, was led by corresponding authors Li Wu and Huapeng Feng alongside co-authors Yingying Tao, Jianing Li, Rui Yang, Jiasheng Song, Jianhong Shu, and Yulong He. Because the replication of influenza A virus fundamentally depends on host cell machinery and involves complex networks of host proteins, identifying the specific cellular regulators that facilitate viral infection remains an important focus of molecular virology. The manuscript was submitted for evaluation on September 27, 2026, and accepted on October 13, 2026.
Subject of Research: Influenza A virus replication and host factor S100A4
Article Title: S100A4 facilitates influenza A virus replication by interacting with M2 in human alveolar epithelial cells
Article References: Wu, L., Tao, Y., Li, J., Yang, R., Song, J., Shu, J., He, Y., & Feng, H. (2026). S100A4 facilitates influenza A virus replication by interacting with M2 in human alveolar epithelial cells. Frontiers in Microbiology, 17, Article 2011614. https://doi.org/10.3389/fmicb.2026.2011614
Image Credits: AI Generated
DOI: 10.3389/fmicb.2026.2011614
Keywords: Influenza A virus, S100A4, M2 protein, viral replication, A549 cells, host factors, innate immunity, polymerase activity, facilitates, influenza, virus, replication
News Source: Kristina Jarvis. (November 7, 2026). Host Factor S100A4 Promotes Influenza A Virus Replication Through M2 Interaction. Scienmag.
