{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T09:03:31Z","timestamp":1785488611913,"version":"3.56.0"},"reference-count":45,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T00:00:00Z","timestamp":1785456000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health NIH-NIAID","award":["R01AI176537"],"award-info":[{"award-number":["R01AI176537"]}]},{"name":"National Institutes of Health NIH-NIAID","award":["R21AI191628"],"award-info":[{"award-number":["R21AI191628"]}]},{"name":"NIH-NIAMS","award":["R21AR080778"],"award-info":[{"award-number":["R21AR080778"]}]},{"name":"NIH-NIAMS","award":["R03TR004595"],"award-info":[{"award-number":["R03TR004595"]}]},{"name":"NIH-NIAMS","award":["AI188584"],"award-info":[{"award-number":["AI188584"]}]},{"name":"NIH-NIAMS","award":["AI149754"],"award-info":[{"award-number":["AI149754"]}]},{"name":"Arizona ABRC","award":["RFGA2024-022 AZ IG"],"award-info":[{"award-number":["RFGA2024-022 AZ IG"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Myhre syndrome is a rare autosomal-dominant disorder caused by gain-of-function (GOF) variants in SMAD4. Although it is primarily recognized as a fibrotic disease, we and others have identified respiratory infection-associated morbidity as a major clinical burden. Regardless, the epithelial-intrinsic mechanisms underlying increased viral susceptibility in Myhre syndrome remain poorly understood. Here, using patient-derived nasal airway epithelial cells (NECs) and respiratory syncytial virus (RSV) infection as a model, we demonstrate that infection is markedly exacerbated in Myhre syndrome epithelium relative to matched healthy controls. We further show that activation of TGF-\u03b21\u2013SMAD4 signaling in healthy donor NECs phenocopies augmented RSV susceptibility, identifying SMAD4 signaling as a bona fide pro-viral pathway in airway epithelium. Mechanistically, we identify a significant reduction in BPIFA1 expression in Myhre syndrome NECs. BPIFA1 is a key secreted innate defense protein with antimicrobial, immunomodulatory, and emerging antiviral functions. SMAD signaling suppresses BPIFA1 expression, and its knockdown in healthy cells mimics the increased viral susceptibility, linking SMAD4 gain-of-function to impaired epithelial immunity. Therapeutically, we evaluated novel, stabilized 24-amino acid BPIFA1-derived peptides as a potential intervention. Treatment with active peptides (A4-153 and A4-X7) significantly reduced RSV infectivity and epithelial damage in both healthy and Myhre syndrome airway epithelial cultures, whereas a scrambled control peptide (A4-198) showed no significant effect. Collectively, our findings establish that GOF SMAD4 signaling enhances viral vulnerability in airway epithelium through suppression of BPIFA1-mediated antiviral defense and demonstrate that BPIFA1-derived peptide therapeutics represent a promising strategy to restore innate antiviral protection.<\/jats:p>","DOI":"10.3390\/biom16081118","type":"journal-article","created":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T08:20:18Z","timestamp":1785486018000},"page":"1118","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["SMAD4\u2013BPIFA1 Axis Governs Airway Antiviral Defense in Myhre Syndrome"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2028-2087","authenticated-orcid":false,"given":"Yuanpu P.","family":"Di","sequence":"first","affiliation":[{"name":"Department of Cellular and Molecular Medicine, Center for Translational Science, Florida International University, Port St. Lucie, FL 34987, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bodong","family":"Wen","sequence":"additional","affiliation":[{"name":"Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, MA 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengyuan","family":"Li","sequence":"additional","affiliation":[{"name":"Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, MA 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felicia","family":"Tang","sequence":"additional","affiliation":[{"name":"Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, MA 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dena","family":"Shen","sequence":"additional","affiliation":[{"name":"Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, MA 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6724-7938","authenticated-orcid":false,"given":"Mark E.","family":"Lindsay","sequence":"additional","affiliation":[{"name":"Cardiovascular Genetics Program, Massachusetts General Hospital, Boston, MA 02114, USA"},{"name":"Cardiovascular Research Center, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1145-4572","authenticated-orcid":false,"given":"Angela E.","family":"Lin","sequence":"additional","affiliation":[{"name":"Medical Genetics, Department of Pediatrics, Mass General for Children, Boston, MA 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2191-6873","authenticated-orcid":false,"given":"Yin","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, School of Pharmacy, The University of Arizona, Tucson, AZ 85721, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6624-7757","authenticated-orcid":false,"given":"Hongmei","family":"Mou","sequence":"additional","affiliation":[{"name":"Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, MA 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1520","DOI":"10.1002\/ajmg.a.35374","article-title":"Mutations of SMAD4 Account for Both LAPS and Myhre Syndromes","volume":"158A","author":"Lindor","year":"2012","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.ajhg.2011.12.011","article-title":"A Restricted Spectrum of Mutations in the SMAD4 Tumor-Suppressor Gene Underlies Myhre Syndrome","volume":"90","author":"Caputo","year":"2012","journal-title":"Am. J. Hum. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Viaut, C., and Cormier-Daire, V. (2026). Review of the Molecular and Developmental Basis of Myhre Syndrome, Bench Research. Am. J. Med. Genet. C Semin. Med. Genet.","DOI":"10.1002\/ajmg.c.70010"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1177\/10935266221079569","article-title":"Review of the Pathologic Characteristics in Myhre Syndrome: Gain-of-Function Pathogenic Variants in SMAD4 Cause a Multisystem Fibroproliferative Response","volume":"25","author":"Starr","year":"2022","journal-title":"Pediatr. Dev. Pathol. Off. J. Soc. Pediatr. Pathol. Paediatr. Pathol. Soc."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1038\/s41392-024-01764-w","article-title":"TGF-\u03b2 Signaling in Health, Disease and Therapeutics","volume":"9","author":"Deng","year":"2024","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e63638","DOI":"10.1002\/ajmg.a.63638","article-title":"Emergence of the Natural History of Myhre Syndrome: 47 Patients Evaluated in the Massachusetts General Hospital Myhre Syndrome Clinic (2016\u20132023)","volume":"194","author":"Lin","year":"2024","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Mittal, S., Johnson, E.F., Schimmenti, L.A., and Mohandesi, N.A. (2026). Review of Cutaneous Manifestations in Myhre Syndrome With Histopathological Analyses and Genotype-Phenotype Correlation. Am. J. Med. Genet. C Semin. Med. Genet.","DOI":"10.1002\/ajmgc.70005"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.jaci.2024.08.024","article-title":"Gain-of-Function Variants in SMAD4 Compromise Respiratory Epithelial Function","volume":"155","author":"Lindsay","year":"2025","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"S131","DOI":"10.1093\/jpids\/piae017","article-title":"A Review of Respiratory Syncytial Virus Epidemiology Among Children: Linking Effective Prevention to Vulnerable Populations","volume":"13","author":"Daniels","year":"2024","journal-title":"J. Pediatr. Infect. Dis. Soc."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Asseri, A.A. (2025). Respiratory Syncytial Virus: A Narrative Review of Updates and Recent Advances in Epidemiology, Pathogenesis, Diagnosis, Management and Prevention. J. Clin. Med., 14.","DOI":"10.3390\/jcm14113880"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Pokharel, S.M., Shil, N.K., and Bose, S. (2016). Autophagy, TGF-\u03b2, and SMAD-2\/3 Signaling Regulates Interferon-\u03b2 Response in Respiratory Syncytial Virus Infected Macrophages. Front. Cell. Infect. Microbiol., 6.","DOI":"10.3389\/fcimb.2016.00174"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1038\/mi.2017.77","article-title":"Epithelial-Derived TGF-\u03921 Acts as a pro-Viral Factor in the Lung during Influenza A Infection","volume":"11","author":"Denney","year":"2018","journal-title":"Mucosal Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"12552","DOI":"10.1038\/s41598-019-49056-6","article-title":"TGF-\u03921 Increases Viral Burden and Promotes HIV-1 Latency in Primary Differentiated Human Bronchial Epithelial Cells","volume":"9","author":"Chinnapaiyan","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Bedke, N., Sammut, D., Green, B., Kehagia, V., Dennison, P., Jenkins, G., Tatler, A., Howarth, P.H., Holgate, S.T., and Davies, D.E. (2012). Transforming Growth Factor-Beta Promotes Rhinovirus Replication in Bronchial Epithelial Cells by Suppressing the Innate Immune Response. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0044580"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"107236","DOI":"10.1016\/j.micpath.2024.107236","article-title":"Recent Advances in TGF-\u03b2 Signaling Pathway in COVID-19 Pathogenesis: A Review","volume":"199","author":"Majidpour","year":"2025","journal-title":"Microb. Pathog."},{"key":"ref_16","first-page":"PA2652","article-title":"Amplified Virus Infection in a Transforming Growth Factor-Beta (TGFB) Transgenic Mouse Model of Inflammatory Lung Disease","volume":"52","author":"Thomas","year":"2018","journal-title":"Eur. Respir. J."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1038\/s41590-026-02458-x","article-title":"TGF-\u03b2 Mediates Epigenetic Control of Innate Antiviral Responses and SIV Reservoir Size","volume":"27","author":"Ghneim","year":"2026","journal-title":"Nat. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e00435-25","DOI":"10.1128\/jvi.00435-25","article-title":"An RGD Motif on SARS-CoV-2 Spike Induces TGF-\u03b2 Signaling and Downregulates Interferon","volume":"99","author":"Gracie","year":"2025","journal-title":"J. Virol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"12424","DOI":"10.1128\/JVI.00806-09","article-title":"Cell Cycle Arrest by Transforming Growth Factor Beta1 Enhances Replication of Respiratory Syncytial Virus in Lung Epithelial Cells","volume":"83","author":"Gibbs","year":"2009","journal-title":"J. Virol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2880","DOI":"10.1128\/JVI.02583-06","article-title":"Transforming Growth Factor Beta Enhances Respiratory Syncytial Virus Replication and Tumor Necrosis Factor Alpha Induction in Human Epithelial Cells","volume":"81","author":"McCann","year":"2007","journal-title":"J. Virol."},{"key":"ref_21","first-page":"10013","article-title":"Airway Serous Cells: A Comparative Study of Spatial Distribution and Abundance among Species","volume":"1","author":"Di","year":"2024","journal-title":"J. Respir. Biol. Transl. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1089\/jir.2020.0141","article-title":"The Multifunctional Roles of Short Palate, Lung, and Nasal Epithelium Clone 1 in Regulating Airway Surface Liquid and Participating in Airway Host Defense","volume":"41","author":"Liu","year":"2021","journal-title":"J. Interferon Cytokine Res. Off. J. Int. Soc. Interferon Cytokine Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2021890","DOI":"10.1155\/2018\/2021890","article-title":"The Role of BPIFA1 in Upper Airway Microbial Infections and Correlated Diseases","volume":"2018","author":"Tsou","year":"2018","journal-title":"BioMed Res. Int."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1643","DOI":"10.1152\/physrev.00039.2023","article-title":"Lung Antimicrobial Proteins and Peptides: From Host Defense to Therapeutic Strategies","volume":"104","author":"Di","year":"2024","journal-title":"Physiol. Rev."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"L321","DOI":"10.1152\/ajplung.00056.2018","article-title":"BPIFA1 Regulates Lung Neutrophil Recruitment and Interferon Signaling during Acute Inflammation","volume":"316","author":"Britto","year":"2019","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Saferali, A., Tang, A.C., Strug, L.J., Quon, B.S., Zlosnik, J., Sandford, A.J., and Turvey, S.E. (2020). Immunomodulatory Function of the Cystic Fibrosis Modifier Gene BPIFA1. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0227067"},{"key":"ref_27","first-page":"2478","article-title":"SPLUNC1 Is an Allosteric Modulator of the Epithelial Sodium Channel","volume":"32","author":"Kim","year":"2018","journal-title":"FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1038\/mi.2017.45","article-title":"An Innate Defense Peptide BPIFA1\/SPLUNC1 Restricts Influenza A Virus Infection","volume":"11","author":"Akram","year":"2018","journal-title":"Mucosal Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2779","DOI":"10.3892\/or.2015.3913","article-title":"SPLUNC1 Reduces the Inflammatory Response of Nasopharyngeal Carcinoma Cells Infected with the EB Virus by Inhibiting the TLR9\/NF-\u03baB Pathway","volume":"33","author":"Ou","year":"2015","journal-title":"Oncol. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1038\/labinvest.2014.162","article-title":"Gammaherpesvirus Infection Modulates the Temporal and Spatial Expression of SCGB1A1 (CCSP) and BPIFA1 (SPLUNC1) in the Respiratory Tract","volume":"95","author":"Leeming","year":"2015","journal-title":"Lab. Investig."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1002\/prca.201100016","article-title":"Innate Immunity Proteins and a New Truncated Form of SPLUNC1 in Nasopharyngeal Aspirates from Infants with Respiratory Syncytial Virus Infection","volume":"5","author":"Fornander","year":"2011","journal-title":"Proteom. Clin. Appl."},{"key":"ref_32","unstructured":"Bai, X., Chen, S., Yin, S., Zhao, Q., Gu, Q., Ran, J., Shi, J., Zhang, Y., Ni, H., and Pu, Y. (2026). Single-Cell RNA Sequencing Reveals Mucosal BPIFA1-High-Expressing Neutrophils Aid Immune Defense in SARS-CoV-2 Breakthrough Infection. J. Infect. Dis., jiag267."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1016\/j.antiviral.2016.08.013","article-title":"Antimicrobial Peptides Alter Early Immune Response to Influenza A Virus Infection in C57BL\/6 Mice","volume":"133","author":"LeMessurier","year":"2016","journal-title":"Antivir. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.stem.2016.05.012","article-title":"Dual SMAD Signaling Inhibition Enables Long-Term Expansion of Diverse Epithelial Basal Cells","volume":"19","author":"Mou","year":"2016","journal-title":"Cell Stem Cell"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e183978","DOI":"10.1172\/JCI183978","article-title":"Activation of STAT3-Mediated Ciliated Cell Survival Protects against Severe Infection by Respiratory Syncytial Virus","volume":"134","author":"Zhao","year":"2024","journal-title":"J. Clin. Investig."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.virol.2010.07.006","article-title":"Roles of the Respiratory Syncytial Virus Trailer Region: Effects of Mutations on Genome Production and Stress Granule Formation","volume":"406","author":"Hanley","year":"2010","journal-title":"Virology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e00226-19","DOI":"10.1128\/mBio.00226-19","article-title":"Antibacterial Properties and Efficacy of a Novel SPLUNC1-Derived Antimicrobial Peptide, A4-Short, in a Murine Model of Respiratory Infection","volume":"10","author":"Jiang","year":"2019","journal-title":"mBio"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"12895","DOI":"10.1128\/JVI.01273-10","article-title":"Transforming Growth Factor Beta Is a Major Regulator of Human Neonatal Immune Responses Following Respiratory Syncytial Virus Infection","volume":"84","author":"Thornburg","year":"2010","journal-title":"J. Virol."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Carlson, C.M., Turpin, E.A., Moser, L.A., O\u2019Brien, K.B., Cline, T.D., Jones, J.C., Tumpey, T.M., Katz, J.M., Kelley, L.A., and Gauldie, J. (2010). Transforming Growth Factor-\u03b2: Activation by Neuraminidase and Role in Highly Pathogenic H5N1 Influenza Pathogenesis. PLoS Pathog., 6.","DOI":"10.1371\/journal.ppat.1001136"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3000","DOI":"10.1016\/j.celrep.2018.08.033","article-title":"Regional Differences in Airway Epithelial Cells Reveal Tradeoff between Defense against Oxidative Stress and Defense against Rhinovirus","volume":"24","author":"Mihaylova","year":"2018","journal-title":"Cell Rep."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"651","DOI":"10.21037\/atm-20-3462","article-title":"Molecular Biology of BPIFB1 and Its Advances in Disease","volume":"8","author":"Li","year":"2020","journal-title":"Ann. Transl. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1007\/s10875-021-01051-1","article-title":"STAT3 Hyper-IgE Syndrome\u2014An Update and Unanswered Questions","volume":"41","author":"Tsilifis","year":"2021","journal-title":"J. Clin. Immunol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e70497","DOI":"10.1002\/hsr2.70497","article-title":"Hyper IgE Syndromes: Understanding, Management, and Future Perspectives: A Narrative Review","volume":"8","author":"Salehi","year":"2025","journal-title":"Health Sci. Rep."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1016\/j.jaci.2022.12.821","article-title":"STAT3 Mutation-Associated Airway Epithelial Defects in Job Syndrome","volume":"152","author":"Zhang","year":"2023","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"101477","DOI":"10.1016\/j.coviro.2025.101477","article-title":"Status of Advanced Respiratory Syncytial Virus Antiviral Therapeutics 2025","volume":"73","author":"Ruckel","year":"2025","journal-title":"Curr. Opin. Virol."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/16\/8\/1118\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T08:51:36Z","timestamp":1785487896000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/16\/8\/1118"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,31]]},"references-count":45,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["biom16081118"],"URL":"https:\/\/doi.org\/10.3390\/biom16081118","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,31]]}}}