{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T09:01:09Z","timestamp":1793178069450,"version":"4.5.0"},"reference-count":28,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T00:00:00Z","timestamp":1761523200000},"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. Microbiol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>In recent years, coinfections of porcine epidemic diarrhea virus (PEDV) with other enteric pathogens have been frequently observed in diarrheal piglets. However, the underlying mechanisms of pathogen\u2013pathogen or pathogen\u2013host interactions during such coinfections remain to be elucidated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this study, an in vitro coinfection test of bovine viral diarrhea virus (BVDV) and PEDV was performed on model cells established before to explore the effect of coinfection on PEDV replication. Additionally, we used small interfering RNA (siRNA) assay to explore the role of TLRs related to NF-\u03baB signaling in response to PEDV and BVDV coinfection.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We found that after preinfection with BVDV, PEDV replicates faster and more easily in PK15 cells. Further analysis revealed that coinfection of PEDV and BVDV significantly induced NF-\u03baB activity, leading to increased translocation of the NF-\u03baB p65 subunit from the cytoplasm to the nucleus. Moreover, TLR7 was identified as a key pattern recognition receptor in this process, mediating NF-\u03baB activation and promoting the expression of inflammatory cytokines.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>These results suggest that synergistic interactions between PEDV and BVDV during coinfection may strongly activate the host immune system and enhance virus replication. This study provides new insights into the immune modulation mechanisms underlying viral coinfections.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmicb.2025.1684847","type":"journal-article","created":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T06:21:48Z","timestamp":1761546108000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["PEDV and BVDV coinfection activates the NF-\u03baB pathway by a TLR7-dependent mechanism"],"prefix":"10.3389","volume":"16","author":[{"given":"Jinghua","family":"Cheng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benqiang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Tao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huili","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,10,27]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"1374","DOI":"10.3390\/cells10061374","article-title":"Toll-like receptor signaling in the establishment and function of the immune system","volume":"10","author":"Aluri","year":"2021","journal-title":"Cells"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"1757","DOI":"10.1099\/vir.0.000133","article-title":"Porcine epidemic diarrhea virus infection induces NF-\u03baB activation through the TLR2, TLR3 and TLR9 pathways in porcine intestinal epithelial cells","volume":"96","author":"Cao","year":"2015","journal-title":"J. Gen. Virol."},{"key":"ref3","first-page":"31","article-title":"Nuclear factor-kappaB: activation and regulation during Toll-like receptor signaling","volume":"4","author":"Carmody","year":"2007","journal-title":"Cell. Mol. Immunol."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1186\/s12985-022-01845-8","article-title":"Coinfection with PEDV and BVDV induces inflammatory bowel disease pathway highly enriched in PK-15 cells","volume":"19","author":"Cheng","year":"2022","journal-title":"Virol. J."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"1884","DOI":"10.1080\/21505594.2022.2135724","article-title":"Identification of key proteins of cytopathic biotype bovine viral diarrhoea virus involved in activating NF-\u03baB pathway in BVDV-induced inflammatory response","volume":"13","author":"Fan","year":"2022","journal-title":"Virulence"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"2332653","DOI":"10.1080\/22221751.2024.2332653","article-title":"Coinfection and nonrandom recombination drive the evolution of swine enteric coronaviruses","volume":"13","author":"Guo","year":"2024","journal-title":"Emerg. Microbes Infect."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1016\/j.virusres.2018.09.012","article-title":"Lethal influenza A virus preferentially activates TLR3 and triggers a severe inflammatory response","volume":"257","author":"Huo","year":"2018","journal-title":"Virus Res."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1016\/j.tvjl.2005.02.016","article-title":"The effects of transplacental porcine circovirus type 2 infection on porcine epidemic diarrhoea virus-induced enteritis in preweaning piglets","volume":"171","author":"Jung","year":"2006","journal-title":"Vet. J."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"687","DOI":"10.1111\/1348-0421.12443","article-title":"Highly pathogenic avian influenza H5N1 virus induces cytokine dysregulation with suppressed maturation of chicken monocyte-derived dendritic cells","volume":"60","author":"Kalaiyarasu","year":"2016","journal-title":"Microbiol. Immunol."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"718","DOI":"10.1354\/vp.43-5-718","article-title":"Potentiation of porcine circovirus 2-induced postweaning multisystemic wasting syndrome by porcine parvovirus is associated with excessive production of tumor necrosis factor-alpha","volume":"43","author":"Kim","year":"2006","journal-title":"Vet. Pathol."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1124\/mol.113.089821","article-title":"Novel small molecule inhibitors of TLR7 and TLR9: mechanism of action and efficacy in vivo","volume":"85","author":"Lamphier","year":"2014","journal-title":"Mol. Pharmacol."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"865283","DOI":"10.3389\/fcimb.2022.865283","article-title":"Nephropathogenic infectious bronchitis virus mediates kidney injury in chickens via the TLR7\/NF-\u03baB signaling axis","volume":"12","author":"Li","year":"2022","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"869","DOI":"10.1002\/jmv.27405","article-title":"Role of Toll-like receptors in modulation of cytokine storm signaling in SARS-CoV-2-induced COVID-19","volume":"94","author":"Manik","year":"2022","journal-title":"J. Med. Virol."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1016\/j.molcel.2006.05.012","article-title":"Toll-like receptors and RNA helicases: two parallel ways to trigger antiviral responses","volume":"22","author":"Meylan","year":"2006","journal-title":"Mol. Cell"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1016\/j.cvfa.2009.10.007","article-title":"Bovine viral diarrhea virus: global status","volume":"26","author":"Ridpath","year":"2010","journal-title":"Vet. Clin. North Am. Food Anim. Pract."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"1101","DOI":"10.1038\/nprot.2008.73","article-title":"Analyzing real-time PCR data by the comparative CT method","volume":"3","author":"Schmittgen","year":"2008","journal-title":"Nat. Protoc."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1159\/000543608","article-title":"RNA viruses, Toll-like receptors, and cytokines: the perfect storm?","volume":"17","author":"Stegeman","year":"2025","journal-title":"J. Innate Immun."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1038\/nrmicro2950","article-title":"West Nile virus infection and immunity","volume":"11","author":"Suthar","year":"2013","journal-title":"Nat. Rev. Microbiol."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/j.smim.2003.10.003","article-title":"TLR signaling pathways","volume":"16","author":"Takeda","year":"2004","journal-title":"Semin. Immunol."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"6729","DOI":"10.1167\/iovs.11-7805","article-title":"Roles played by Toll-like receptor-9 in corneal endothelial cells after herpes simplex virus type 1 infection","volume":"52","author":"Takeda","year":"2011","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1016\/j.vetmic.2013.03.010","article-title":"Bovine viral diarrhea virus (BVDV) infections in pigs","volume":"165","author":"Tao","year":"2013","journal-title":"Vet. Microbiol."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"604","DOI":"10.1111\/j.1462-5822.2008.01277.x","article-title":"Human TLR3 recognizes dengue virus and modulates viral replication in vitro","volume":"11","author":"Tsai","year":"2009","journal-title":"Cell. Microbiol."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"31332","DOI":"10.1074\/jbc.M103217200","article-title":"Endocytosed HSP60s use Toll-like receptor 2 (TLR2) and TLR4 to activate the Toll\/interleukin-1 receptor signaling pathway in innate immune cells","volume":"276","author":"Vabulas","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1016\/j.virol.2018.07.014","article-title":"Toll-like receptor agonist R848 blocks Zika virus replication by inducing the antiviral protein viperin","volume":"522","author":"Vanwalscappel","year":"2018","journal-title":"Virology"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"9144","DOI":"10.3390\/ijms25179144","article-title":"Rabies virus regulates inflammatory response in BV-2 cells through activation of Myd88 and NF-\u03baB signaling pathways via TLR7","volume":"25","author":"Xie","year":"2024","journal-title":"Int. J. Mol. Sci."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"1303915","DOI":"10.3389\/fmicb.2024.1303915","article-title":"Epidemiological monitoring and genetic variation analysis of pathogens associated with porcine viral diarrhea in southern China from 2021 to 2023","volume":"15","author":"Zhang","year":"2024","journal-title":"Front. Microbiol."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"msad052","DOI":"10.1093\/molbev\/msad052","article-title":"Global dynamics of porcine enteric coronavirus PEDV epidemiology, evolution, and transmission","volume":"40","author":"Zhang","year":"2023","journal-title":"Mol. Biol. Evol."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"55","DOI":"10.4149\/av_2016_01_55","article-title":"The rate of co-infection for piglet diarrhea viruses in China and the genetic characterization of porcine epidemic diarrhea virus and porcine kobuvirus","volume":"60","author":"Zhao","year":"2016","journal-title":"Acta Virol."}],"container-title":["Frontiers in Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2025.1684847\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T06:21:49Z","timestamp":1761546109000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2025.1684847\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,27]]},"references-count":28,"alternative-id":["10.3389\/fmicb.2025.1684847"],"URL":"https:\/\/doi.org\/10.3389\/fmicb.2025.1684847","relation":{},"ISSN":["1664-302X"],"issn-type":[{"value":"1664-302X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,27]]},"article-number":"1684847"}}