How hMPV rewires host RNA splicing to promote viral replication

Human metapneumovirus (hMPV) is a globally circulating respiratory virus responsible for substantial morbidity among infants, elderly individuals, and immunocompromised patients. Despite its significant public health burden, no licensed vaccines or virus-specific therapeutics are currently available. Understanding how hMPV manipulates host cellular machinery remains a critical challenge in developing effective antiviral strategies.

Using affinity purification coupled with mass spectrometry, transcriptome sequencing, genetic perturbation, and advanced imaging approaches, researchers systematically mapped interactions between hMPV proteins and host cellular factors. Among the viral proteins examined, M2-2 was found to interact directly with multiple heterogeneous nuclear ribonucleoproteins (hnRNPs), including hnRNP H1, hnRNP M, and hnRNP U, all of which are involved in regulating mRNA splicing. Transcriptome analysis revealed widespread alterations in host alternative splicing following M2-2 expression. More than 1,400 alternative splicing events affecting over 1,000 host genes were identified. Among these, STRAP and TANC2 emerged as critical targets of M2-2-mediated splicing regulation. Functional experiments further showed that knockout of STRAP or TANC2 significantly reduced viral replication.

“Our findings reveal an unexpected role for the hMPV M2-2 protein beyond its previously recognized functions in viral replication and immune modulation,” said Dr. Ke Zhang, corresponding author of the study and a researcher at the Shanghai Institute of Materia Medica, Chinese Academy of Sciences. “M2-2 acts as a molecular bridge that connects the virus to the host splicing machinery, allowing the virus to reshape cellular gene expression for its own benefit.”

The mechanism relies on M2-2 binding to specific hnRNP complexes in the nucleus. Comparative infection assays demonstrate that these splicing events are unique to hMPV, underlining a virus-specific strategy. This work combines biochemical, genetic, and imaging approaches to validate M2-2’s role in hijacking the host spliceosome.

These findings broaden current understanding of hMPV biology and identify the interface between M2-2 and host splicing factors as a potential therapeutic vulnerability. Future work will focus on determining the structural basis of M2-2–hnRNP interactions and exploring whether pharmacological disruption of this pathway can suppress viral infection.

This work was conducted by researchers from the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, the National Institute for Viral Disease Control and Prevention of the Chinese Center for Disease Control and Prevention, Fudan University Eye and ENT Hospital, and collaborating institutions. The study provides a foundation for developing host-directed antiviral strategies against hMPV and related respiratory pathogens.

About Author: 

Dr. Ke Zhang is a principal investigator at the Shanghai Institute of Materia Medica, Chinese Academy of Sciences. His research focuses on virus-host interactions, RNA virus biology, and the discovery of host-directed antiviral targets. His laboratory integrates molecular virology and RNA biology to uncover mechanisms by which viruses manipulate host cellular pathways and to identify novel therapeutic strategies against emerging infectious diseases. For more information, please visit to Dr. Zhang' s research homepage https://simm.cas.cn/sourcedb/zw/gb2020/yjzz/202509/t20250926_7981050.html.

DOI Link:

https://doi.org/10.1016/j.hlife.2026.03.005