{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T23:47:55Z","timestamp":1791244075241,"version":"4.1.0"},"reference-count":122,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,9,29]],"date-time":"2022-09-29T00:00:00Z","timestamp":1664409600000},"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:p>\n                    Recognition of viral infection by pattern recognition receptors is paramount for a successful immune response to viral infection. However, an unbalanced proinflammatory response can be detrimental to the host. Recently, multiple studies have identified that the SARS-CoV-2 spike protein activates Toll-like receptor 4 (TLR4), resulting in the induction of proinflammatory cytokine expression. Activation of TLR4 by viral glycoproteins has also been observed in the context of other viral infection models, including respiratory syncytial virus (RSV), dengue virus (DENV) and Ebola virus (EBOV). However, the mechanisms involved in virus-TLR4 interactions have remained unclear. Here, we review viral glycoproteins that act as pathogen-associated molecular patterns to induce an immune response\n                    <jats:italic>via<\/jats:italic>\n                    TLR4. We explore the current understanding of the mechanisms underlying how viral glycoproteins are recognized by TLR4 and discuss the contribution of TLR4 activation to viral pathogenesis. We identify contentious findings and research gaps that highlight the importance of understanding viral glycoprotein-mediated TLR4 activation for potential therapeutic approaches.\n                  <\/jats:p>","DOI":"10.3389\/fmicb.2022.1007081","type":"journal-article","created":{"date-parts":[[2022,9,29]],"date-time":"2022-09-29T08:11:10Z","timestamp":1664439070000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":62,"title":["Activation of TLR4 by viral glycoproteins: A double-edged sword?"],"prefix":"10.3389","volume":"13","author":[{"given":"Emily A.","family":"Halajian","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuelle V.","family":"LeBlanc","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katrina","family":"Gee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Che C.","family":"Colpitts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,9,29]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"881","DOI":"10.1126\/science.1247749","article-title":"Flavivirus NS1 structures reveal surfaces for associations with membranes and the immune system","volume":"343","author":"Akey","year":"2014","journal-title":"Science"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1038\/nri1391","article-title":"Toll-like receptor signalling","volume":"4","author":"Akira","year":"2004","journal-title":"Nat. Rev. Immunol."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"4464","DOI":"10.2174\/1381612827666210716160030","article-title":"Interaction of ectodomain of respiratory syncytial virus G protein with TLR2\/TLR6 heterodimer: an in vitro and in silico approach to decipher the role of RSV G protein in proinflammatory response against the virus","volume":"27","author":"Alshaghdali","year":"2021","journal-title":"Curr. Pharm. Design."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1038\/76048","article-title":"TLR4 mutations are associated with endotoxin hyporesponsiveness in humans","volume":"25","author":"Arbour","year":"2000","journal-title":"Nat. Genet."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"3171","DOI":"10.4049\/jimmunol.179.5.3171","article-title":"Association of TLR4 polymorphisms with symptomatic respiratory syncytial virus infection in high-risk infants and young children","volume":"179","author":"Awomoyi","year":"2007","journal-title":"J. Immunol."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1152\/physiolgenomics.00128.2004","article-title":"The induction of macrophage gene expression by LPS predominantly utilizes Myd 88-independent signaling cascades","volume":"19","author":"Bj\u00f6rkbacka","year":"2004","journal-title":"Physiol. Genomics"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"12191","DOI":"10.1128\/JVI.01604-08","article-title":"The secreted form of respiratory syncytial virus g glycoprotein helps the virus evade antibody-mediated restriction of replication by acting as an antigen decoy and through effects on fc receptor-bearing leukocytes","volume":"82","author":"Bukreyev","year":"2008","journal-title":"J. Virol."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2014\/901276","article-title":"elevated dengue virus nonstructural protein 1 serum levels and altered toll-like receptor 4 expression, nitric oxide, and tumor necrosis factor alpha production in dengue hemorrhagic fever patients","volume":"2014","author":"Carvalho","year":"2014","journal-title":"J. Trop. Med."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"e1007625","DOI":"10.1371\/journal.ppat.1007625","article-title":"Dengue virus nonstructural protein 1 activates platelets via Toll-like receptor 4, leading to thrombocytopenia and hemorrhage","volume":"15","author":"Chao","year":"2019","journal-title":"PLoS Pathog."},{"key":"ref10","doi-asserted-by":"crossref","DOI":"10.1101\/2021.06.14.448426","article-title":"Proinflammatory responses in SARS-CoV-2 infected and soluble spike glycoprotein S1 subunit activated human macrophages","volume-title":"bioRxiv","author":"Chiok","year":"2021"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"1233","DOI":"10.1007\/s00018-020-03656-y","article-title":"TLR4 and CD14 trafficking and its influence on LPS-induced proinflammatory signaling","volume":"78","author":"Ciesielska","year":"2021","journal-title":"Cell. Mol. Life Sci."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1007\/s10565-021-09693-y","article-title":"SARS-CoV-2 Spike protein is not proinflammatory in human primary macrophages: endotoxin contamination and lack of protein glycosylation as possible confounders","volume":"38","author":"Cinquegrani","year":"2022","journal-title":"Cell Biol. Toxicol."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"2318","DOI":"10.3390\/ijms18112318","article-title":"The Role of Carbohydrates in the Lipopolysaccharide (LPS)\/Toll-Like Receptor 4 (TLR4) Signalling","volume":"18","author":"Cochet","year":"2017","journal-title":"Int. J. Mol. Sci."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"e0197420","DOI":"10.1128\/JVI.01974-20","article-title":"Apo A1 neutralizes proinflammatory effects of dengue virus NS1 protein and modulates viral immune evasion","volume":"95","author":"Coelho","year":"2021","journal-title":"J. Virol."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"e1003258","DOI":"10.1371\/journal.ppat.1003258","article-title":"The secret life of viral entry glycoproteins: moonlighting in immune evasion","volume":"9","author":"Cook","year":"2013","journal-title":"PLoS Pathog."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"1845","DOI":"10.1074\/jbc.M109910200","article-title":"MD-2 and TLR4 N-linked glycosylations are Important for a functional lipopolysaccharide receptor","volume":"277","author":"da Silva Correia","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"19839","DOI":"10.1038\/s41598-020-76836-2","article-title":"Similarities and differences between the \u2018cytokine storms\u2019 in acute dengue and COVID-19","volume":"10","author":"Dayarathna","year":"2020","journal-title":"Sci. Rep."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1016\/j.mehy.2015.05.009","article-title":"Treatment of Ebola virus infections with inhibitors of TLR4","volume":"85","author":"Denner","year":"2015","journal-title":"Med. Hypotheses"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"352","DOI":"10.4269\/ajtmh.2011.10-0728","article-title":"Toll-like receptor 4 polymorphisms in dengue virus\u2013infected children","volume":"85","author":"Djamiatun","year":"2011","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"1305","DOI":"10.3390\/microorganisms9061305","article-title":"Dengue virus induces the expression and release of endocan from endothelial cells by an NS1\u2013TLR4-dependent mechanism","volume":"9","author":"Dom\u00ednguez-Alem\u00e1n","year":"2021","journal-title":"Microorganisms"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"1146","DOI":"10.1002\/eji.200324449","article-title":"The role of Toll-like receptor 4 versus interleukin-12 in immunity to respiratory syncytial virus","volume":"34","author":"Ehl","year":"2004","journal-title":"Eur. J. Immunol."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"e1004509","DOI":"10.1371\/journal.ppat.1004509","article-title":"Shed GP of ebola virus triggers immune activation and increased vascular permeability","volume":"10","author":"Escudero-P\u00e9rez","year":"2014","journal-title":"PLoS Pathog."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"2255","DOI":"10.1056\/NEJMra2026131","article-title":"Cytokine storm","volume":"383","author":"Fajgenbaum","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1016\/j.bbi.2021.12.007","article-title":"SARS-CoV-2 spike S1 subunit induces neuroinflammatory, microglial and behavioral sickness responses: Evidence of PAMP-like properties","volume":"100","author":"Frank","year":"2022","journal-title":"Brain Behav. Immun."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"304","DOI":"10.1016\/j.virol.2006.12.032","article-title":"Vesicular stomatitis virus glycoprotein G activates a specific antiviral Toll-like receptor 4-dependent pathway","volume":"362","author":"Georgel","year":"2007","journal-title":"Virology"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"e1006673","DOI":"10.1371\/journal.ppat.1006673","article-title":"Dengue virus NS1 cytokine-independent vascular leak is dependent on endothelial glycocalyx components","volume":"13","author":"Glasner","year":"2017","journal-title":"PLoS Pathog."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"9859","DOI":"10.1073\/pnas.151098198","article-title":"Cleavage of the human respiratory syncytial virus fusion protein at two distinct sites is required for activation of membrane fusion","volume":"98","author":"Gonz\u00e1lez-Reyes","year":"2001","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1124\/pr.114.010090","article-title":"Toll-like Receptors in the Vascular System: Sensing the Dangers Within","volume":"68","author":"Goulopoulou","year":"2016","journal-title":"Pharmacol. Rev."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"16055","DOI":"10.1038\/nrdp.2016.55","article-title":"Dengue infection","volume":"2","author":"Guzman","year":"2016","journal-title":"Nat. Rev. Dis. Primers."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"1199","DOI":"10.1086\/344644","article-title":"Respiratory syncytial virus\u2013induced activation of nuclear factor\u2013\u03baB in the lung involves alveolar macrophages and toll-like receptor 4\u2013dependent pathways","volume":"186","author":"Haeberle","year":"2002","journal-title":"J. Infect. Dis."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"2640","DOI":"10.3389\/fimmu.2018.02640","article-title":"Respiratory viral infection-induced microbiome alterations and secondary bacterial pneumonia","volume":"9","author":"Hanada","year":"2018","journal-title":"Front. Immunol."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"10730","DOI":"10.1128\/JVI.75.22.10730-10737.2001","article-title":"Involvement of toll-like receptor 4 in innate immunity to respiratory syncytial virus","volume":"75","author":"Haynes","year":"2001","journal-title":"J. Virol."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"1225","DOI":"10.1093\/intimm\/dxf089","article-title":"Differential involvement of IFN-b in Toll-like receptor-stimulated dendritic cell activation","volume":"14","author":"Hoshino","year":"2002","journal-title":"Int. Immunol."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"S327","DOI":"10.1093\/infdis\/jiy406","article-title":"Ebola virus shed glycoprotein triggers differentiation, infection, and death of monocytes through Toll-like receptor 4 activation","volume":"218","author":"Iampietro","year":"2018","journal-title":"J. Infect. Dis."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"e1006397","DOI":"10.1371\/journal.ppat.1006397","article-title":"Ebola virus glycoprotein directly triggers T lymphocyte death despite of the lack of infection","volume":"13","author":"Iampietro","year":"2017","journal-title":"PLoS Pathog."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1038\/ni1207","article-title":"CD14 is required for MyD88-independent LPS signaling","volume":"6","author":"Jiang","year":"2005","journal-title":"Nat. Immunol."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"576","DOI":"10.1038\/s41586-022-04702-4","article-title":"Fc\u03b3 R-mediated SARS-CoV-2 infection of monocytes activates inflammation","volume":"606","author":"Junqueira","year":"2022","journal-title":"Nature"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"943","DOI":"10.1016\/j.cell.2006.03.047","article-title":"Phosphoinositide-mediated adaptor recruitment controls Toll-like receptor signaling","volume":"125","author":"Kagan","year":"2006","journal-title":"Cells"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1038\/ni1569","article-title":"TRAM couples endocytosis of Toll-like receptor 4 to the induction of interferon-\u03b2","volume":"9","author":"Kagan","year":"2008","journal-title":"Nat. Immunol."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1080\/14728222.2021.1918103","article-title":"TLR4 as a therapeutic target for respiratory and neurological complications of SARS-CoV-2","volume":"25","author":"Kaushik","year":"2021","journal-title":"Expert. Opin. Ther. Tar."},{"key":"ref44","doi-asserted-by":"publisher","first-page":"460","DOI":"10.1016\/j.molmed.2007.09.002","article-title":"Signaling to NF-\u03baB by Toll-like receptors","volume":"13","author":"Kawai","year":"2007","journal-title":"Trends Mol. Med."},{"key":"ref45","doi-asserted-by":"publisher","first-page":"5887","DOI":"10.4049\/jimmunol.167.10.5887","article-title":"Lipopolysaccharide stimulates the MyD88-independent pathway and results in activation of IFN-regulatory factor 3 and the expression of a subset of lipopolysaccharide-inducible genes","volume":"167","author":"Kawai","year":"2001","journal-title":"J. Immunol."},{"key":"ref46","doi-asserted-by":"publisher","first-page":"744233","DOI":"10.3389\/fmicb.2021.744233","article-title":"Recent insights into the molecular mechanism of Toll-like receptor response to dengue virus infection","volume":"12","author":"Kayesh","year":"2021","journal-title":"Front. Microbiol."},{"key":"ref47","doi-asserted-by":"publisher","first-page":"e68563","DOI":"10.7554\/eLife.68563","article-title":"SARS-CoV-2 spike protein induces inflammation via TLR2-dependent activation of the NF-\u03baB pathway","volume":"10","author":"Khan","year":"2021","journal-title":"elife"},{"key":"ref48","doi-asserted-by":"publisher","first-page":"906","DOI":"10.1016\/j.cell.2007.08.002","article-title":"Crystal structure of the TLR4-MD-2 complex with bound endotoxin antagonist eritoran","volume":"130","author":"Kim","year":"2007","journal-title":"Cells"},{"key":"ref49","doi-asserted-by":"publisher","first-page":"398","DOI":"10.1038\/80833","article-title":"Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virus","volume":"1","author":"Kurt-Jones","year":"2000","journal-title":"Nat. Immunol."},{"key":"ref50","doi-asserted-by":"publisher","first-page":"34","DOI":"10.3390\/vaccines5040034","article-title":"TLR4 signaling pathway modulators as potential therapeutics in inflammation and sepsis","volume":"5","author":"Kuzmich","year":"2017","journal-title":"Vaccine"},{"key":"ref51","doi-asserted-by":"publisher","first-page":"1571","DOI":"10.3389\/fmicb.2017.01571","article-title":"Ebola virus glycoprotein induces an innate immune response in vivo via TLR4","volume":"8","author":"Lai","year":"2017","journal-title":"Front. Microbiol."},{"key":"ref52","doi-asserted-by":"publisher","first-page":"1246","DOI":"10.1016\/j.jmb.2013.11.024","article-title":"Toll-like receptors in antiviral innate immunity","volume":"426","author":"Lester","year":"2014","journal-title":"J. Mol. Biol."},{"key":"ref53","doi-asserted-by":"publisher","first-page":"1165","DOI":"10.1086\/343813","article-title":"High circulating levels of the dengue virus nonstructural protein NS1 early in dengue illness correlate with the development of dengue hemorrhagic fever","volume":"186","author":"Libraty","year":"2002","journal-title":"J. Infect. Dis."},{"key":"ref54","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1177\/1753425908095957","article-title":"Host species-specific usage of the TLR4-LPS receptor complex","volume":"14","author":"Lizundia","year":"2008","journal-title":"Innate Immunol."},{"key":"ref55","doi-asserted-by":"publisher","first-page":"1028","DOI":"10.1001\/archinte.162.9.1028","article-title":"Relevance of mutations in the TLR4 receptor in patients with Gram-negative septic shock","volume":"162","author":"Lorenz","year":"2002","journal-title":"Arch. Intern. Med."},{"key":"ref56","doi-asserted-by":"publisher","first-page":"538","DOI":"10.1016\/j.stemcr.2022.01.015","article-title":"A human pluripotent stem cell-based model of SARS-CoV-2 infection reveals an ACE2-independent inflammatory activation of vascular endothelial cells through TLR4","volume":"17","author":"Ma","year":"2022","journal-title":"Stem. Cell. Rep."},{"key":"ref57","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1016\/S1473-3099(04)01103-X","article-title":"Pathogenesis of filoviral haemorrhagic fevers","volume":"4","author":"Mahanty","year":"2004","journal-title":"Lancet Infect. Dis."},{"key":"ref58","doi-asserted-by":"publisher","first-page":"155151","DOI":"10.1016\/j.cyto.2020.155151","article-title":"COVID-19 cytokine storm: the anger of inflammation","volume":"133","author":"Mahmudpour","year":"2020","journal-title":"Cytokine"},{"key":"ref59","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":"2021","journal-title":"J. Med. Virol."},{"key":"ref60","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1002\/JLB.3MIR1218-483RR","article-title":"Below the surface: the inner lives of TLR4 and TLR9","volume":"106","author":"Marongiu","year":"2019","journal-title":"J. Leukoc. Biol."},{"key":"ref61","doi-asserted-by":"publisher","first-page":"856","DOI":"10.1177\/1753425912444479","article-title":"Role of human TLR4 in respiratory syncytial virus-induced NF-\u03baB activation, viral entry and replication","volume":"18","author":"Marr","year":"2012","journal-title":"Innate Immunol."},{"key":"ref62","doi-asserted-by":"publisher","first-page":"1091","DOI":"10.2217\/fvl.11.79","article-title":"Clinical aspects of Marburg hemorrhagic fever","volume":"6","author":"Mehedi","year":"2011","journal-title":"Futur. Virol."},{"key":"ref63","doi-asserted-by":"publisher","first-page":"475","DOI":"10.1126\/science.1232578","article-title":"Direct proteomic quantification of the secretome of activated immune cells","volume":"340","author":"Meissner","year":"2013","journal-title":"Science"},{"key":"ref64","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1038\/icb.2017.5","article-title":"Dengue virus NS1 protein activates immune cells via TLR4 but not TLR2 or TLR6","volume":"95","author":"Modhiran","year":"2017","journal-title":"Immunol. Cell Biol."},{"key":"ref65","doi-asserted-by":"publisher","first-page":"304ra142","DOI":"10.1126\/scitranslmed.aaa3863","article-title":"Dengue virus NS1 protein activates cells via Toll-like receptor 4 and disrupts endothelial cell monolayer integrity","volume":"7","author":"Modhiran","year":"2015","journal-title":"Sci. Transl. Med."},{"key":"ref66","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2016\/6978936","article-title":"The role of Toll-like receptor 4 in infectious and noninfectious inflammation","volume":"2016","author":"Molteni","year":"2016","journal-title":"Mediat. Inflamm."},{"key":"ref67","doi-asserted-by":"publisher","first-page":"53035","DOI":"10.1074\/jbc.M308093200","article-title":"respiratory syncytial virus up-regulates TLR4 and sensitizes airway epithelial cells to endotoxin","volume":"278","author":"Monick","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref68","doi-asserted-by":"crossref","DOI":"10.1101\/2021.06.20.448993","article-title":"Selectively expressing SARS-CoV-2 Spike protein S1 subunit in cardiomyocytes induces cardiac hypertrophy in mice","volume-title":"bioRxiv","author":"Negron","year":"2021"},{"key":"ref69","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1038\/nri2079","article-title":"The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling","volume":"7","author":"O\u2019Neill","year":"2007","journal-title":"Nat. Rev. Immunol."},{"key":"ref70","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1128\/JVI.01462-09","article-title":"Interaction between ebola virus glycoprotein and host Toll-like receptor 4 leads to induction of proinflammatory cytokines and SOCS1","volume":"84","author":"Okumura","year":"2010","journal-title":"J. Virol."},{"key":"ref71","doi-asserted-by":"publisher","first-page":"10399","DOI":"10.1128\/JVI.01736-15","article-title":"Suppressor of cytokine signaling 3 is an inducible host factor that regulates virus egress during ebola virus infection","volume":"89","author":"Okumura","year":"2015","journal-title":"J. Virol."},{"key":"ref72","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1007\/s12035-021-02593-6","article-title":"SARS-CoV-2 spike glycoprotein S1 induces neuroinflammation in BV-2 microglia","volume":"59","author":"Olajide","year":"2022","journal-title":"Mol. Neurobiol."},{"key":"ref73","doi-asserted-by":"publisher","first-page":"1865","DOI":"10.1007\/s10753-021-01464-5","article-title":"Induction of exaggerated cytokine production in human peripheral blood mononuclear cells by a recombinant SARS-CoV-2 spike glycoprotein S1 and its inhibition by dexamethasone","volume":"44","author":"Olajide","year":"2021","journal-title":"Inflammation"},{"key":"ref74","doi-asserted-by":"publisher","first-page":"e00179","DOI":"10.1128\/JVI.00179-17","article-title":"Ebolaviruses associated with differential pathogenicity induce distinct host responses in human macrophages","volume":"91","author":"Olejnik","year":"2017","journal-title":"J. Virol."},{"key":"ref75","doi-asserted-by":"publisher","first-page":"e1007390","DOI":"10.1371\/journal.ppat.1007390","article-title":"Toll-like receptor 4 in acute viral infection: Too much of a good thing","volume":"14","author":"Olejnik","year":"2018","journal-title":"PLoS Pathog."},{"key":"ref76","doi-asserted-by":"publisher","first-page":"721","DOI":"10.1016\/j.bbrc.2010.04.169","article-title":"TLR4-mediated activation of mouse macrophages by Korean mistletoe lectin-C (KML-C)","volume":"396","author":"Park","year":"2010","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref77","doi-asserted-by":"publisher","first-page":"e66","DOI":"10.1038\/emm.2013.97","article-title":"Recognition of lipopolysaccharide pattern by TLR4 complexes","volume":"45","author":"Park","year":"2013","journal-title":"Exp. Mol. Med."},{"key":"ref78","doi-asserted-by":"publisher","first-page":"1191","DOI":"10.1038\/nature07830","article-title":"The structural basis of lipopolysaccharide recognition by the TLR4\u2013MD-2 complex","volume":"458","author":"Park","year":"2009","journal-title":"Nature"},{"key":"ref79","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1016\/j.clim.2007.03.003","article-title":"Common human Toll-like receptor 4 polymorphisms\u2014Role in susceptibility to respiratory syncytial virus infection and functional immunological relevance","volume":"123","author":"Paulus","year":"2007","journal-title":"Clin. Immunol."},{"key":"ref80","doi-asserted-by":"publisher","first-page":"40791","DOI":"10.1038\/srep40791","article-title":"TLR4 antagonist FP7 inhibits LPS-induced cytokine production and glycolytic reprogramming in dendritic cells, and protects mice from lethal influenza infection","volume":"7","author":"Perrin-Cocon","year":"2017","journal-title":"Sci. Rep."},{"key":"ref81","doi-asserted-by":"publisher","first-page":"1230","DOI":"10.3390\/v12111230","article-title":"Association of genetic polymorphisms in TLR3, TLR4, TLR7, and TLR8 with the clinical forms of dengue in patients from veracruz","volume":"12","author":"Posadas-Mondrag\u00f3n","year":"2020","journal-title":"Mexico. Viruses"},{"key":"ref82","doi-asserted-by":"publisher","first-page":"e1005738","DOI":"10.1371\/journal.ppat.1005738","article-title":"Dengue virus NS1 disrupts the endothelial glycocalyx, leading to hyperpermeability","volume":"12","author":"Puerta-Guardo","year":"2016","journal-title":"PLoS Pathog."},{"key":"ref83","doi-asserted-by":"publisher","first-page":"2018","DOI":"10.1182\/bloodadvances.2019001169","article-title":"Inflammatory signaling in dengue-infected platelets requires translation and secretion of nonstructural protein 1","volume":"4","author":"Quirino-Teixeira","year":"2020","journal-title":"Blood Adv."},{"key":"ref84","doi-asserted-by":"publisher","first-page":"1446","DOI":"10.3389\/fimmu.2020.01446","article-title":"The COVID-19 cytokine storm; what we know so far","volume":"11","author":"Ragab","year":"2020","journal-title":"Front. Immunol."},{"key":"ref85","doi-asserted-by":"publisher","first-page":"e00218","DOI":"10.1128\/mBio.00218-12","article-title":"Respiratory syncytial virus fusion protein-induced toll-like receptor 4 (TLR4) signaling is inhibited by the TLR4 antagonists Rhodobacter sphaeroides lipopolysaccharide and eritoran (E 5564) and requires direct interaction with MD-2","volume":"3","author":"Rallabhandi","year":"2012","journal-title":"MBio"},{"key":"ref86","doi-asserted-by":"publisher","first-page":"1820","DOI":"10.3389\/fimmu.2017.01820","article-title":"Targeting and recognition of Toll-like receptors by plant and pathogen lectins","volume":"8","author":"Ricci-Azevedo","year":"2017","journal-title":"Front. Immunol."},{"key":"ref87","doi-asserted-by":"publisher","first-page":"4538","DOI":"10.1128\/jvi.68.7.4538-4546.1994","article-title":"The membrane-associated and secreted forms of the respiratory syncytial virus attachment glycoprotein G are synthesized from alternative initiation codons","volume":"68","author":"Roberts","year":"1994","journal-title":"J. Virol."},{"key":"ref88","doi-asserted-by":"publisher","first-page":"1424","DOI":"10.2174\/092986712799828346","article-title":"Inflammatory responses to respiratory syncytial virus (RSV) infection and the development of immunomodulatory pharmacotherapeutics","volume":"19","author":"Rosenberg","year":"2012","journal-title":"Curr. Med. Chem."},{"key":"ref89","author":"Scherm","year":"2022"},{"key":"ref90","doi-asserted-by":"publisher","first-page":"831763","DOI":"10.3389\/fimmu.2022.831763","article-title":"The S1 subunit of the SARS-CoV-2 spike protein activates human monocytes to produce cytokines linked to COVID-19: relevance to galectin-3","volume":"13","author":"Schroeder","year":"2022","journal-title":"Front. Immunol."},{"key":"ref91","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1101\/2021.09.27.461948","article-title":"Inflammasome activation in infected macrophages drives COVID-19 pathology","volume":"606","author":"Sefik","year":"2022","journal-title":"Nature"},{"key":"ref92","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1016\/j.meegid.2016.06.027","article-title":"Analysis of TLR4 (Asp 299Gly and Thr 399Ile) gene polymorphisms and mRNA level in patients with dengue infection: A case-control study","volume":"43","author":"Sharma","year":"2016","journal-title":"Infect. Genet. Evol."},{"key":"ref93","doi-asserted-by":"publisher","first-page":"1169","DOI":"10.1093\/intimm\/dxn074","article-title":"Soluble G protein of respiratory syncytial virus inhibits Toll-like receptor 3\/4-mediated IFN-beta induction","volume":"20","author":"Shingai","year":"2008","journal-title":"Int. Immunol."},{"key":"ref95","doi-asserted-by":"publisher","first-page":"e06187","DOI":"10.1016\/j.heliyon.2021.e06187","article-title":"SARS-CoV-2 spike protein S1 subunit induces proinflammatory responses via toll-like receptor 4 signaling in murine and human macrophages","volume":"7","author":"Shirato","year":"2021","journal-title":"Heliyon"},{"key":"ref96","doi-asserted-by":"publisher","first-page":"705080","DOI":"10.3389\/fimmu.2021.705080","article-title":"Targeting TLR4 signaling to blunt viral-mediated acute lung injury","volume":"12","author":"Shirey","year":"2021","journal-title":"Front. Immunol."},{"key":"ref97","doi-asserted-by":"publisher","first-page":"498","DOI":"10.1038\/nature12118","article-title":"The TLR4 antagonist Eritoran protects mice from lethal influenza infection","volume":"497","author":"Shirey","year":"2013","journal-title":"Nature"},{"key":"ref98","doi-asserted-by":"publisher","first-page":"e343","DOI":"10.3346\/jkms.2020.35.e343","article-title":"COVID-19 patients upregulate Toll-like receptor 4-mediated inflammatory signaling that mimics bacterial sepsis","volume":"35","author":"Sohn","year":"2020","journal-title":"J. Korean Med. Sci."},{"key":"ref99","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1016\/j.virol.2011.02.022","article-title":"N-linked glycosylation of dengue virus NS1 protein modulates secretion, cell-surface expression, hexamer stability, and interactions with human complement","volume":"413","author":"Somnuke","year":"2011","journal-title":"Virology"},{"key":"ref100","doi-asserted-by":"publisher","first-page":"563","DOI":"10.1007\/s00281-017-0625-1","article-title":"Immune-mediated cytokine storm and its role in severe dengue","volume":"39","author":"Srikiatkhachorn","year":"2017","journal-title":"Semin. Immunopathol."},{"key":"ref101","doi-asserted-by":"publisher","first-page":"3902","DOI":"10.1016\/j.vaccine.2019.05.026","article-title":"Glucopyranosyl lipid adjuvant enhances immune response to Ebola virus-like particle vaccine in mice","volume":"37","author":"Sunay","year":"2019","journal-title":"Vaccine"},{"key":"ref102","doi-asserted-by":"crossref","DOI":"10.1101\/2022.06.14.22276401","article-title":"Persistent circulating SARS-CoV-2 spike is associated with post-acute COVID-19 sequelae","volume-title":"medRxiv","author":"Swank","year":"2022"},{"key":"ref103","doi-asserted-by":"publisher","first-page":"6293","DOI":"10.2147\/JIR.S343246","article-title":"Toll-like receptor 4 polymorphisms (896A\/G and 1196C\/T) as an indicator of COVID-19 severity in a convenience sample of egyptian patients","volume":"14","author":"Taha","year":"2021","journal-title":"J. Inflamm. Res."},{"key":"ref104","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":"ref105","doi-asserted-by":"publisher","first-page":"2057","DOI":"10.1086\/420830","article-title":"Association between common Toll-like receptor 4 mutations and severe respiratory syncytial virus disease","volume":"189","author":"Tal","year":"2004","journal-title":"J. Infect. Dis."},{"key":"ref106","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1007\/s12664-020-01114-y","article-title":"Toll-like receptor 4 (TLR4) antagonists as potential therapeutics for intestinal inflammation","volume":"40","author":"Tam","year":"2021","journal-title":"Indian J. Gastroenterol."},{"key":"ref107","doi-asserted-by":"publisher","first-page":"909","DOI":"10.1016\/j.immuni.2015.10.008","article-title":"Mechanisms of Toll-like receptor 4 endocytosis reveal a common immune-evasion strategy used by pathogenic and commensal bacteria","volume":"43","author":"Tan","year":"2015","journal-title":"Immunity"},{"key":"ref108","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1016\/j.bbrc.2008.01.061","article-title":"Roles for LPS-dependent interaction and relocation of TLR4 and TRAM in TRIF-signaling","volume":"368","author":"Tanimura","year":"2008","journal-title":"Biochem. Bioph. Res. Co."},{"key":"ref109","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1254\/fpj.21041","article-title":"Contribution to development of remedies for COVID-19: focusing on Eritoran","volume":"157","author":"Tsukahara","year":"2022","journal-title":"Nihon Yakurigaku Zasshi"},{"key":"ref110","doi-asserted-by":"publisher","first-page":"1324","DOI":"10.1016\/j.bcp.2011.03.010","article-title":"Plant lectins are novel Toll-like receptor agonists","volume":"81","author":"Unitt","year":"2011","journal-title":"Biochem. Pharmacol."},{"key":"ref111","doi-asserted-by":"publisher","first-page":"646","DOI":"10.1002\/eji.202149656","article-title":"SARS-CoV-2 infection activates dendritic cells via cytosolic receptors rather than extracellular TLRs","volume":"52","author":"van der Donk","year":"2022","journal-title":"Eur. J. Immunol."},{"key":"ref112","doi-asserted-by":"publisher","first-page":"3936","DOI":"10.1172\/JCI132438","article-title":"Ebola virus glycoprotein stimulates IL-18\u2013dependent natural killer cell responses","volume":"130","author":"Wagstaffe","year":"2020","journal-title":"J. Clin. Invest."},{"key":"ref113","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1038\/cmi.2011.1","article-title":"Mannan-binding lectin directly interacts with Toll-like receptor 4 and suppresses lipopolysaccharide-induced inflammatory cytokine secretion from THP-1 cells","volume":"8","author":"Wang","year":"2011","journal-title":"Cell. Mol. Immunol."},{"key":"ref114","doi-asserted-by":"publisher","first-page":"1480","DOI":"10.1016\/j.bbagen.2019.05.012","article-title":"Exploitation of glycosylation in enveloped virus pathobiology","volume":"1863","author":"Watanabe","year":"2019","journal-title":"Biochim. Biophys. Acta Gen. Subj."},{"key":"ref115","doi-asserted-by":"publisher","first-page":"715","DOI":"10.1016\/j.imbio.2007.09.010","article-title":"Role of Toll-like receptor responses for sepsis pathogenesis","volume":"212","author":"Weighardt","year":"2008","journal-title":"Immunobiology"},{"key":"ref116","doi-asserted-by":"publisher","first-page":"2823","DOI":"10.4049\/jimmunol.169.6.2823","article-title":"Cutting edge: myeloid differentiation factor 88 deficiency improves resistance against sepsis caused by polymicrobial infection","volume":"169","author":"Weighardt","year":"2002","journal-title":"J. Immunol."},{"key":"ref117","doi-asserted-by":"publisher","first-page":"1428","DOI":"10.1016\/S0140-6736(14)62384-9","article-title":"Severe Ebola virus disease with vascular leakage and multiorgan failure: treatment of a patient in intensive care","volume":"385","author":"Wolf","year":"2015","journal-title":"Lancet"},{"key":"ref118","doi-asserted-by":"publisher","first-page":"640","DOI":"10.1126\/science.1087262","article-title":"Role of adaptor trif in the MYD88-independent Toll-like receptor signaling pathway","volume":"301","author":"Yamamoto","year":"2003","journal-title":"Science"},{"key":"ref119","doi-asserted-by":"publisher","first-page":"324","DOI":"10.1038\/nature01182","article-title":"Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4","volume":"420","author":"Yamamoto","year":"2002","journal-title":"Nature"},{"key":"ref120","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2010\/240365","article-title":"Current Views of Toll-Like Receptor Signaling Pathways","volume":"2010","author":"Yamamoto","year":"2010","journal-title":"Gastroenterol. Res. Pract."},{"key":"ref121","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1038\/s41392-022-00968-2","article-title":"Aptamer blocking S-TLR4 interaction selectively inhibits SARS-CoV-2 induced inflammation","volume":"7","author":"Yang","year":"2022","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref122","doi-asserted-by":"publisher","first-page":"e00845","DOI":"10.1128\/mBio.00845-17","article-title":"Ebola virus binding to Tim-1 on T lymphocytes induces a cytokine storm","volume":"8","author":"Younan","year":"2017","journal-title":"MBio"},{"key":"ref123","doi-asserted-by":"publisher","first-page":"868","DOI":"10.1016\/j.cell.2011.09.051","article-title":"CD14 controls the LPS-Induced endocytosis of toll-like receptor 4","volume":"147","author":"Zanoni","year":"2011","journal-title":"Cells"},{"key":"ref124","doi-asserted-by":"publisher","first-page":"818","DOI":"10.1038\/s41422-021-00495-9","article-title":"SARS-CoV-2 spike protein interacts with and activates TLR4","volume":"31","author":"Zhao","year":"2021","journal-title":"Cell Res."},{"key":"ref125","doi-asserted-by":"publisher","first-page":"526965","DOI":"10.3389\/fimmu.2020.526965","article-title":"Respiratory syncytial virus F subunit vaccine with AS02 adjuvant elicits balanced, robust humoral and cellular immunity in BALB\/c mice","volume":"11","author":"Zheng","year":"2020","journal-title":"Front. Immunol."},{"key":"ref126","doi-asserted-by":"publisher","first-page":"829","DOI":"10.1038\/s41590-021-00937-x","article-title":"TLR2 senses the SARS-CoV-2 envelope protein to produce inflammatory cytokines","volume":"22","author":"Zheng","year":"2021","journal-title":"Nat. Immunol."}],"container-title":["Frontiers in Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2022.1007081\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,9,29]],"date-time":"2022-09-29T08:11:16Z","timestamp":1664439076000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2022.1007081\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,29]]},"references-count":122,"alternative-id":["10.3389\/fmicb.2022.1007081"],"URL":"https:\/\/doi.org\/10.3389\/fmicb.2022.1007081","relation":{},"ISSN":["1664-302X"],"issn-type":[{"value":"1664-302X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,29]]},"article-number":"1007081"}}