Respiratory syncytial virus (RSV) is the leading pathogen worldwide causing lower respiratory tract infections in infants and young children, and it also poses a serious threat to older adults and immunocompromised populations, resulting in a substantial disease burden and deaths each year. Although RSV has a simple structure, its complex interactions with the host are highly dependent on post-translational modifications (PTMs). Acting as molecular switches that rapidly regulate protein function, localization, and stability, these modifications play decisive roles in the viral life cycle and host immune responses. This article systematically reviews the multiple roles of PTMs in RSV infection, with a focus on how glycosylation of the viral G and F proteins influences viral tropism, receptor binding, and immune evasion, and how phosphorylation of the N and P proteins finely regulates the formation and function of the viral replication complex (inclusion bodies). It also analyzes how RSV creates a favorable environment for replication by hijacking host kinase networks and the ubiquitination system to remodel the cytoskeleton, suppress type I interferon responses, and regulate apoptosis. A deeper understanding of these mechanisms will not only help elucidate RSV pathogenesis but also has important translational value, particularly by informing structure-based vaccine antigen design (e.g., optimizing epitope exposure) and providing key strategies for developing novel antiviral drugs that target host PTM enzymes and are less prone to resistance.

Ya Gao, Daishun Liu. Post-Translational Modifications in Respiratory Syncytial Virus Infection: Orchestrating Host-Pathogen Interactions. Frontiers in Medical Science Research (2026), Vol. 8, Issue 1: 24-31. https://doi.org/10.25236/FMSR.2026.080103.

[1] Battles MB, McLellan JS. Respiratory syncytial virus entry and how to block it.Nat Rev Microbiol. 2019;17(4):233-245. doi:10.1038/s41579-019-0149-x

[2] Nam HH, Ison MG. Respiratory syncytial virus infection in adults.BMJ. 2019;366:l5021. doi:10.1136/bmj.l5021

[3] Wang Y, Zheng J, Wang X, Yang P, Zhao D. Alveolar macrophages and airway hyperresponsiveness associated with respiratory syncytial virus infection.Front Immunol. 2022;13:1012048. doi:10.3389/fimmu.2022.1012048

[4] Griffiths C, Drews SJ, Marchant DJ. Respiratory syncytial virus: infection, detection, and new options for prevention and treatment. Clin Microbiol Rev. 2017;30(1):277-319. doi:10.1128/CMR.00010-16

[5] Tayyari F, Marchant D, Moraes TJ, Duan W, Mastrangelo P, Hegele RG. Identification of nucleolin as a cellular receptor for human respiratory syncytial virus. Nat Med. 2011;17(9):1132-1135. doi:10.1038/nm.2444

[6] Galloux M, Risso-Ballester J, Richard CA, Fix J, Rameix-Welti MA, Eléouët JF. Minimal Elements Required for the Formation of Respiratory Syncytial Virus Cytoplasmic Inclusion Bodies In Vivo and In Vitro. mBio. 2020;11(5):e01202- e01220. Published 2020 Sep 22. doi:10.1128/mBio.01202-20

[7] Kumar R, Mehta D, Mishra N, Nayak D, Sunil S. Role of host-mediated post-translational modifications (PTMs) in RNA virus pathogenesis.Int J Mol Sci. 2020;22(1):323. doi:10.3390/ijms22010323

[8] Chamontin C, Bossis G, Nisole S, Arhel NJ, Maarifi G. Regulation of viral restriction by post-translational modifications.Viruses. 2021;13(11):2197. doi:10.3390/v13112197

[9] Ben Khlifa E, Campese A, Corsi A, et al. Post-translational modifications in respiratory virus infection: recent insights into the development of in vitro models.Int J Mol Sci. 2025;26(24):12174. doi:10.3390/ijms262412174

[10] Xiao J, Han Y, Liu K, et al. Post-translational modifications: bridging viral infections and inflammatory bowel disease.Mol Aspects Med. 2025;106:101417. doi:10.1016/j.mam.2025.101417

[11] Xiao Y, Gao M, Mo X, et al. Mechanisms and research methods of protein modification in virus entry. Appl Biochem Biotechnol. 2025;197(10):6283-6313. doi:10.1007/s12010-025-05333-x

[12] Leemans A, Boeren M, Van der Gucht W, et al. Characterization of the role of N-glycosylation sites in the respiratory syncytial virus fusion protein in virus replication, syncytium formation and antigenicity.Virus Res. 2019;266:58-68. doi:10.1016/j.virusres.2019.04.006

[13] Rixon HWM, Brown C, Brown G, Sugrue RJ. Multiple glycosylated forms of the respiratory syncytial virus fusion protein are expressed in virus-infected cells.J Gen Virol. 2002;83(Pt 1):61-66. doi:10.1099/0022-1317-83-1-61

[14] Leemans A, Boeren M, Van der Gucht W, et al. Removal of the N-glycosylation sequon at position N116 located in p27 of the respiratory syncytial virus fusion protein elicits enhanced antibody responses after DNA immunization.Viruses. 2018;10(8):426. doi:10.3390/v10080426

[15] O'Rourke SM, Murray J, Juarez MG, Tripp RA, DuBois RM. Restricting O-linked glycosylation of the mucin-like domains enhances immunogenicity and protective efficacy of a respiratory syncytial virus G glycoprotein vaccine antigen.Vaccines (Basel). 2025;13(10):1004. Published 2025 Sep 25. doi:10.3390/vaccines13101004

[16] King T, Mejias A, Ramilo O, Peeples ME. The larger attachment glycoprotein of respiratory syncytial virus produced in primary human bronchial epithelial cultures reduces infectivity for cell lines.PLoS Pathog. 2021;17(4):e1009469. doi:10.1371/journal.ppat.1009469

[17] Hallak LK, Spillmann D, Collins PL, Peeples ME. Glycosaminoglycan sulfation requirements for respiratory syncytial virus infection.J Virol. 2000;74(22):10508-10513. doi:10.1128/jvi.74.22.10508-10513.2000

[18] Basse V, Wang Y, Rodrigues-Machado C, et al. Regulation of respiratory syncytial virus nucleoprotein oligomerization by phosphorylation. J Biol Chem. 2025;301(3):108256. doi:10.1016/j.jbc.2025.108256

[19] Villanueva N, Hardy R, Asenjo A, Yu Q, Wertz G. The bulk of the phosphorylation of human respiratory syncytial virus phosphoprotein is not essential but modulates viral RNA transcription and replication.J Gen Virol. 2000;81(Pt 1):129-133. doi:10.1099/0022-1317-81-1-129

[20] Asenjo A, Calvo E, Villanueva N. Phosphorylation of human respiratory syncytial virus P protein at threonine 108 controls its interaction with the M2-1 protein in the viral RNA polymerase complex. J Gen Virol. 2006;87(12):3637-3642. doi:10.1099/vir.0.82165-0

[21] Tanner SJ, Ariza A, Richard CA, et al. Crystal structure of the essential transcription antiterminator M2-1 protein of human respiratory syncytial virus and implications of its phosphorylation.Proc Natl Acad Sci U S A. 2014;111(4):1580-1585. doi:10.1073/pnas.1317262111

[22] Ghildyal R, Teng MN, Tran KC, et al. Nuclear transport of respiratory syncytial virus matrix protein is regulated by dual phosphorylation sites.Int J Mol Sci. 2022;23(14):7976. doi:10.3390/ijms23147976

[23] Martín-Vicente M, Resino S, Martínez I. Early innate immune response triggered by the human respiratory syncytial virus and its regulation by ubiquitination/deubiquitination processes.J Biomed Sci. 2022;29(1):11. doi:10.1186/s12929-022-00793-3

[24] Whelan JN, Tran KC, van Rossum DB, Teng MN. Identification of respiratory syncytial virus nonstructural protein 2 residues essential for exploitation of the host ubiquitin system and inhibition of innate immune responses.J Virol. 2016;90(14):6453-6463. doi:10.1128/JVI.00423-16

[25] Ban J, Lee NR, Lee NJ, Lee JK, Quan FS, Inn KS. Human respiratory syncytial virus NS 1 targets TRIM25 to suppress RIG-I ubiquitination and subsequent RIG-I-mediated antiviral signaling. Viruses. 2018;10(12):716. doi:10.3390/v10120716

[26] Tanaka Y, Morita N, Kitagawa Y, Gotoh B, Komatsu T. Human metapneumovirus M2-2 protein inhibits RIG-I signaling by preventing TRIM25-mediated RIG-I ubiquitination.Front Immunol. 2022;13:970750. doi:10.3389/fimmu.2022.970750

[27] Elliott J, Lynch OT, Suessmuth Y, et al. Respiratory syncytial virus NS1 protein degrades STAT2 by using the Elongin-Cullin E3 ligase.J Virol. 2007;81(7):3428-3436. doi:10.1128/JVI.02303-06

[28] Okura T, Takahashi T, Kameya T, et al. MARCH8 restricts RSV replication by promoting cellular apoptosis through ubiquitin-mediated proteolysis of viral SH protein.Viruses. 2024;16(12):1935. doi:10.3390/v16121935

[29] Xue M, Zhao BS, Zhang Z, et al. Viral N6-methyladenosine upregulates replication and pathogenesis of human respiratory syncytial virus.Nat Commun. 2019;10(1):4595. doi:10.1038/s41467-019-12504-y

[30] Xue M, Zhang Y, Wang H, et al. Viral RNA N6-methyladenosine modification modulates both innate and adaptive immune responses of human respiratory syncytial virus.PLoS Pathog. 2021;17(12):e1010142. doi:10.1371/journal.ppat.1010142

[31] Sutto-Ortiz P, Tcherniuk S, Ysebaert N, et al. The methyltransferase domain of the respiratory syncytial virus L protein catalyzes cap N7 and 2'-O-methylation.PLoS Pathog. 2021;17(5):e1009562. doi:10.1371/journal.ppat.1009562

[32] Pischedda S, Rivero-Calle I, Gómez-Carballa A, et al. Role and diagnostic performance of host epigenome in respiratory morbidity after RSV infection: the EPIRESVi study. Front Immunol. 2022;13:875691. doi:10.3389/fimmu.2022.875691

[33] Spalluto CM, Singhania A, Cellura D, et al. IFN-γ influences epithelial antiviral responses via histone methylation of the RIG-I promoter.Am J Respir Cell Mol Biol. 2017;57(4):428-438. doi:10.1165/rcmb.2016-0392OC