Mary Wilson
Well-known member
21 January 2025
https://doi.org/10.1128/jvi.01243-24
Pau Ribó-Molina, Kevin Groen, Balasubramanian Susma, Stefan van Nieuwkoop, Mathis Funk, Ron A. M. Fouchier, Bernadette G. van den Hoogen
ABSTRACT
Human metapneumovirus (HMPV) is an important causative agent of respiratory tract disease. Fundamental knowledge of the interaction between HMPV and the innate immune system could lead to the design of novel antiviral therapies. Previously, we demonstrated that HMPV M2-2 deletion mutants had hypermutated genomes and contained defective interfering particles (DIs), which are potent inducers of the IFN response. Here, we investigated the role of the HMPV M2-2 protein as IFN antagonist using chimeric HMPV expressing M2 proteins of other pneumoviruses: respiratory syncytial virus (RSV) and avian metapneumovirus type C (AMPV/C). Chimeric HMPVs expressing the M2 proteins of RSV or AMPV/C were attenuated in HEp-2 cells but did not activate the IFN response, and their genomes were not hypermutated. In contrast, chimeric HMPVs expressing the M2-2 proteins of RSV and AMPV/C, in combination with HMPV M2-1, did activate the IFN response, and their genomes were hypermutated. Investigation of the role of the pneumovirus M2 proteins in transcription regulation demonstrated that the M2-2 protein, only in concerted action with autologous M2-1 protein, acted as a transcription elongation factor. As a second approach, chimeric RSV in which the IFN antagonists NS1 and NS2 were replaced by the HMPV M2-2 gene failed to suppress an IFN response, indicating that the HMPV M2-2 protein is not a potent IFN antagonist. These data indicate that expression of autologous M2-1 and M2-2 proteins is important for the fidelity of the RNA-dependent RNA polymerase, necessary to prevent the accumulation of mutations, and possibly DIs, thereby preventing activation of the IFN responses.
https://journals.asm.org/doi/10.1128/jvi.01243-24
https://doi.org/10.1128/jvi.01243-24
Pau Ribó-Molina, Kevin Groen, Balasubramanian Susma, Stefan van Nieuwkoop, Mathis Funk, Ron A. M. Fouchier, Bernadette G. van den Hoogen
ABSTRACT
Human metapneumovirus (HMPV) is an important causative agent of respiratory tract disease. Fundamental knowledge of the interaction between HMPV and the innate immune system could lead to the design of novel antiviral therapies. Previously, we demonstrated that HMPV M2-2 deletion mutants had hypermutated genomes and contained defective interfering particles (DIs), which are potent inducers of the IFN response. Here, we investigated the role of the HMPV M2-2 protein as IFN antagonist using chimeric HMPV expressing M2 proteins of other pneumoviruses: respiratory syncytial virus (RSV) and avian metapneumovirus type C (AMPV/C). Chimeric HMPVs expressing the M2 proteins of RSV or AMPV/C were attenuated in HEp-2 cells but did not activate the IFN response, and their genomes were not hypermutated. In contrast, chimeric HMPVs expressing the M2-2 proteins of RSV and AMPV/C, in combination with HMPV M2-1, did activate the IFN response, and their genomes were hypermutated. Investigation of the role of the pneumovirus M2 proteins in transcription regulation demonstrated that the M2-2 protein, only in concerted action with autologous M2-1 protein, acted as a transcription elongation factor. As a second approach, chimeric RSV in which the IFN antagonists NS1 and NS2 were replaced by the HMPV M2-2 gene failed to suppress an IFN response, indicating that the HMPV M2-2 protein is not a potent IFN antagonist. These data indicate that expression of autologous M2-1 and M2-2 proteins is important for the fidelity of the RNA-dependent RNA polymerase, necessary to prevent the accumulation of mutations, and possibly DIs, thereby preventing activation of the IFN responses.
https://journals.asm.org/doi/10.1128/jvi.01243-24