{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T00:50:16Z","timestamp":1793407816277,"version":"4.5.0"},"reference-count":30,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T00:00:00Z","timestamp":1773100800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Interferon-based local therapy is an intervention for high-risk human papillomavirus (HR-HPV)-associated low-grade squamous intraepithelial lesions (LSIL) or lower-grade cervical abnormalities. This study sought to delineate the differences in clinical outcomes following interferon-based local drug treatment and elucidate the microenvironmental factors driving these disparities.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Cervical secretions, cell brush specimens, and cervical tissue samples were collected from patients with persistent HR-HPV infection and LSIL\/lower-grade lesions at Shanghai First Maternity and Infant Hospital. Follow-up samples were obtained at 3 months post-treatment. Cervical secretions were subjected to 16S rRNA sequencing (to profile the microbiota) and cytokine quantification. Cell brush specimens were analyzed via transcriptome sequencing, while cervical tissue samples underwent immunohistochemical staining. Efficacy-related markers were assessed through both inter-group (independent comparisons) and intra-patient (self-paired) analyses.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      At the transcriptome level, the HR-HPV clearance group exhibited lower enrichment in pathways related to differentiation, keratinization, and development but higher enrichment in immune activation pathways compared to the persistence group at baseline (with a reversed pattern observed at follow-up). Baseline expression of\n                      <jats:italic>TRAF3IP3, ZBP1<\/jats:italic>\n                      , and\n                      <jats:italic>IFI35<\/jats:italic>\n                      was higher in the clearance group, and\n                      <jats:italic>ZDHHC11<\/jats:italic>\n                      expression remained consistently elevated. Immunohistochemical findings further demonstrated that the percentage of TRAF3IP3- and ZBP1-positive cells at baseline was significantly higher in the clearance group than in the persistence group. At the microbial level, treatment failure was associated with reduced\n                      <jats:italic>Lactobacillus<\/jats:italic>\n                      abundance, increased\n                      <jats:italic>Gardnerella<\/jats:italic>\n                      ,\n                      <jats:italic>Streptococcus anginosus<\/jats:italic>\n                      ,\n                      <jats:italic>Schaalia turicensis<\/jats:italic>\n                      , and\n                      <jats:italic>Comamonadaceae<\/jats:italic>\n                      abundance, alongside higher alpha diversity. Among cervical secretory cytokines, IL-2, IL-8, IL-12p70 showed inter-group differences, while IL-4 and IL-5 were barely detectable.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study characterizes the cervical microenvironmental differences underlying divergent responses to interferon-based therapy, highlighting that coordinated changes in the microenvironment and immune status modulate treatment outcomes. The upregulated mRNA and protein levels of TRAF3IP3 and ZBP1 in the baseline period favor HR-HPV clearance, suggesting their potential as promising therapeutic targets.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcimb.2026.1734088","type":"journal-article","created":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T06:43:17Z","timestamp":1773124997000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["A prospective cohort study on the association between cervical microenvironmental factors and the efficacy of treating high-risk human papillomavirus infection comorbid with cervical diseases"],"prefix":"10.3389","volume":"16","author":[{"given":"Lingyun","family":"Ji","sequence":"first","affiliation":[{"name":"Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University","place":["Shanghai, China"]},{"name":"Shanghai Sci-Tech Inno Center for Infection & Immunity","place":["Shanghai, China"]},{"name":"Department of Laboratory Medicine, Shanghai East Hospital, Tongji University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University","place":["Shanghai, China"]},{"name":"Shanghai Sci-Tech Inno Center for Infection & Immunity","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University","place":["Shanghai, China"]},{"name":"Shanghai Sci-Tech Inno Center for Infection & Immunity","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaowen","family":"Pu","sequence":"additional","affiliation":[{"name":"Department of Cervix, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Cervix, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bowen","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Traditional Chinese Medicine, Shanghai East Hospital, Tongji University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruixian","family":"Jiao","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital of Henan Polytechnic University, The Second People\u2019s Hospital of Jiaozuo","place":["Jiaozuo, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjuan","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Shanghai East Hospital, Tongji University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenhong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University","place":["Shanghai, China"]},{"name":"Shanghai Sci-Tech Inno Center for Infection & Immunity","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,10]]},"reference":[{"key":"B3","doi-asserted-by":"publisher","first-page":"e191","DOI":"10.1016\/S2214-109X(19)30482-6","article-title":"Estimates of incidence and mortality of cervical cancer in 2018: a worldwide analysis","volume":"8","author":"Arbyn","year":"2020","journal-title":"Lancet Glob Health"},{"key":"B2","volume-title":"China human papillomavirus and related cancers, fact sheet","year":"2023"},{"key":"B25","doi-asserted-by":"publisher","first-page":"1975","DOI":"10.1038\/s41467-023-37377-0","article-title":"Single cell transcriptomic analysis of HPV16-infected epithelium identifies a keratinocyte subpopulation implicated in cancer","volume":"14","author":"Bedard","year":"2023","journal-title":"Nat. Commun."},{"key":"B19","doi-asserted-by":"publisher","first-page":"994","DOI":"10.3390\/ph3040994","article-title":"Antiproliferative properties of type I and type II interferon","volume":"3","author":"Bekisz","year":"2010","journal-title":"Pharm. (Basel)"},{"key":"B20","doi-asserted-by":"publisher","first-page":"2193","DOI":"10.1038\/s41467-020-16014-0","article-title":"TRAF3IP3 negatively regulates cytosolic RNA induced anti-viral signaling by promoting TBK1 K48 ubiquitination","volume":"11","author":"Deng","year":"2020","journal-title":"Nat. Commun."},{"key":"B14","doi-asserted-by":"publisher","first-page":"316","DOI":"10.2174\/0113892029293113240427065916","article-title":"HPV16 genomes: in silico analysis of E6 and E7 oncoproteins in 20 south american variants","volume":"25","author":"de Paula Filho","year":"2024","journal-title":"Curr. Genomics"},{"key":"B16","doi-asserted-by":"publisher","first-page":"441","DOI":"10.2174\/0115665232285216240228071244","article-title":"ZNF695, A potential prognostic biomarker, correlates with immune infiltrates in cervical squamous cell carcinoma and endocervical adenocarcinoma: bioinformatic analysis and experimental verification","volume":"24","author":"Ding","year":"2024","journal-title":"Curr. Gene Ther."},{"key":"B10","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1186\/s40168-020-00934-6","article-title":"VALENCIA: a nearest centroid classification method for vaginal microbial communities based on composition","volume":"8","author":"France","year":"2020","journal-title":"Microbiome"},{"key":"B7","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1038\/s41564-022-01083-2","article-title":"Towards a deeper understanding of the vaginal microbiota","volume":"7","author":"France","year":"2022","journal-title":"Nat. Microbiol."},{"key":"B18","first-page":"7632","article-title":"Meta-analysis of the effect and safety of recombinant human interferon \u03b1-2b combined with Baofukang suppository in the treatment of HPV infection","volume":"14","author":"He","year":"2022","journal-title":"Am. J. Transl. Res."},{"key":"B15","doi-asserted-by":"publisher","first-page":"376","DOI":"10.2174\/0109298665390494250513110604","article-title":"Cell-free expression of HPV16 minor capsid protein L2 and its interaction with S100A10","volume":"32","author":"Jiang","year":"2025","journal-title":"Protein Pept. Lett."},{"key":"B500","doi-asserted-by":"publisher","first-page":"215","DOI":"10.3967\/bes2025.117","article-title":"Application of cervical secretion cytokines in high-grade squamous intraepithelial lesions caused by high-risk human papillomavirus infection[J]","volume":"39","author":"Ji","year":"2026","journal-title":"Biomedical and Environmental Sciences"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.abo6294","article-title":"ZBP1-dependent inflammatory cell death, PANoptosis, and cytokine storm disrupt IFN therapeutic efficacy during coronavirus infection","volume":"7","author":"Karki","year":"2022","journal-title":"Sci. Immunol."},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.919728","article-title":"Host and microbiome interplay shapes the vaginal microenvironment","volume":"13","author":"Kwon","year":"2022","journal-title":"Front. Immunol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1016\/j.semcancer.2022.03.005","article-title":"Vaginal microbiome and cervical cancer","volume":"86","author":"Kyrgiou","year":"2022","journal-title":"Semin. Cancer Biol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1076","DOI":"10.1038\/s41467-022-28724-8","article-title":"HPV infection alters vaginal microbiome through down-regulating host mucosal innate peptides used by Lactobacilli as amino acid sources","volume":"13","author":"Lebeau","year":"2022","journal-title":"Nat. Commun."},{"key":"B29","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1186\/s11658-024-00598-2","article-title":"ZBP1 inhibits the replication of Senecavirus A by enhancing NF-\u03baB signaling pathway mediated antiviral response in porcine alveolar macrophage 3D4\/21 cells","volume":"29","author":"Li","year":"2024","journal-title":"Cell Mol. Biol. Lett."},{"key":"B21","doi-asserted-by":"publisher","first-page":"907","DOI":"10.1038\/cmi.2017.146","article-title":"ZDHHC11 modulates innate immune response to DNA virus by mediating MITA-IRF3 association","volume":"15","author":"Liu","year":"2018","journal-title":"Cell Mol. Immunol."},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1128\/MRA.00836-21","article-title":"Complete genome sequence of schaalia turicensis strain CT001, isolated from a patient with gonococcal urethritis in Thailand","volume":"10","author":"Nokchan","year":"2021","journal-title":"Microbiol. Resour Announc"},{"key":"B1","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1111\/1471-0528.15854","article-title":"The vaginal microbiota, human papillomavirus and cervical dysplasia: a systematic review and network meta-analysis","volume":"127","author":"Norenhag","year":"2020","journal-title":"Bjog"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2022.927131","article-title":"Role of immunity and vaginal microbiome in clearance and persistence of human papillomavirus infection","volume":"12","author":"Ntuli","year":"2022","journal-title":"Front. Cell Infect. Microbiol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1128\/CMR.00075-15","article-title":"The human microbiome during bacterial vaginosis","volume":"29","author":"Onderdonk","year":"2016","journal-title":"Clin. Microbiol. Rev."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1868","DOI":"10.1021\/acschembio.4c00110","article-title":"Exploring protein S-palmitoylation: mechanisms, detection, and strategies for inhibitor discovery","volume":"19","author":"Pei","year":"2024","journal-title":"ACS Chem. Biol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"4680","DOI":"10.1073\/pnas.1002611107","article-title":"Vaginal microbiome of reproductive-age women","volume":"108","author":"Ravel","year":"2011","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B24","doi-asserted-by":"publisher","first-page":"626","DOI":"10.1590\/0103-6440201902805","article-title":"Oropharyngeal squamous cell carcinoma: human papilloma virus coinfection with streptococcus anginosus","volume":"30","author":"Robayo","year":"2019","journal-title":"Braz. Dent. J."},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2022.959793","article-title":"Vaginal microecological characteristics of women in different physiological and pathological period","volume":"12","author":"Shen","year":"2022","journal-title":"Front. Cell Infect. Microbiol."},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1008376","article-title":"Cervicovaginal microbiome and natural history of HPV in a longitudinal study","volume":"16","author":"Usyk","year":"2020","journal-title":"PloS Pathog."},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.2174\/1874467216666230217151946","article-title":"Hsa_Circ_0000021 sponges miR-3940-3p\/KPNA2 expression to promote cervical cancer progression","volume":"17","author":"Zeng","year":"2024","journal-title":"Curr. Mol. Pharmacol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"106397","DOI":"10.1016\/j.jinf.2024.106397","article-title":"Ureaplasma parvum serovar 6 may be a novel element in the progression of HPV infection to CIN: A cross-sectional study of 7058 women","volume":"90","author":"Zhang","year":"2025","journal-title":"J. Infect."},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1128\/mmbr.00181-21","article-title":"Roles of the microbiota of the female reproductive tract in gynecological and reproductive health","volume":"86","author":"Zhu","year":"2022","journal-title":"Microbiol. Mol. Biol. Rev."}],"container-title":["Frontiers in Cellular and Infection Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2026.1734088\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T06:43:19Z","timestamp":1773124999000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2026.1734088\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,10]]},"references-count":30,"alternative-id":["10.3389\/fcimb.2026.1734088"],"URL":"https:\/\/doi.org\/10.3389\/fcimb.2026.1734088","relation":{},"ISSN":["2235-2988"],"issn-type":[{"value":"2235-2988","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,10]]},"article-number":"1734088"}}