{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T23:47:48Z","timestamp":1791244068383,"version":"4.1.0"},"reference-count":109,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T00:00:00Z","timestamp":1781222400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The SARS-CoV-2 spike protein has been shown to activate Toll-like receptor 4 (TLR4), yet the precise molecular structures driving recognition and subsequent activation remain poorly defined. Here, we present in silico structural alignments and molecular docking simulations indicating potential spatial compatibility between the wild-type SARS-CoV-2 HR1HR2 fusion core and the human TLR4\/MD-2 heterodimer. The computational models project candidate interfaces involving salt bridges, as well as polar and non-polar interactions, with both TLR4 and MD-2 dimerization partners, suggesting a theoretical topology compatible with the dimerization of two TLR4\/MD-2 heterocomplexes. Notably, similar structural compatibility was modeled for related class I fusion proteins from other highly pathogenic viruses, including SARS-CoV, MERS-CoV, influenza viruses A, B, and C, respiratory syncytial virus (RSV), and partially Ebola virus. These findings offer an exploratory computational hypothesis regarding viral\u2013host interactions with the host innate immune system, which can trigger immune recognition or detrimental hyperactivation.<\/jats:p>","DOI":"10.3390\/ijms27125317","type":"journal-article","created":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T06:53:10Z","timestamp":1781247190000},"page":"5317","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["In Silico Modeling of Structural Compatibility and Alignment Between Viral Class I Fusion Cores and Human TLR4\/MD-2"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4863-6705","authenticated-orcid":false,"given":"Ralf","family":"Kircheis","sequence":"first","affiliation":[{"name":"Advanced Medical Solutions (AMS) Saal, 93342 Saal an der Donau, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"515","DOI":"10.3906\/sag-2004-133","article-title":"Understanding dynamics of pandemics","volume":"50","author":"Akin","year":"2020","journal-title":"Turk. J. Med. Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1186\/s12985-022-01902-2","article-title":"Narrative review on century of respiratory pandemics from Spanish flu to COVID-19 and impact of nanotechnology on COVID-19 diagnosis and immune system boosting","volume":"19","author":"Elkhatib","year":"2022","journal-title":"Virol. J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e18","DOI":"10.1016\/j.jinf.2020.07.002","article-title":"A comparison of mortality-related risk factors of COVID-19, SARS, and MERS: A systematic review and meta-analysis","volume":"81","author":"Lu","year":"2020","journal-title":"J. Infect."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Abdelrahman, Z., Li, M., and Wang, X. (2020). Comparative Review of SARS-CoV-2, SARS-CoV, MERS-CoV, and Influenza A Respiratory Viruses. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.552909"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"5045","DOI":"10.1007\/s00018-020-03557-0","article-title":"Revisiting respiratory syncytial virus\u2019s interaction with host immunity, towards novel therapeutics","volume":"77","author":"Efstathiou","year":"2020","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1007\/978-1-4614-0980-9_9","article-title":"Influenza virus entry","volume":"726","author":"Luo","year":"2012","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1146\/annurev-virology-092818-015708","article-title":"Ebola Virus: Pathogenesis and Countermeasure Development","volume":"6","author":"Furuyama","year":"2019","journal-title":"Annu. Rev. Virol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"102375","DOI":"10.1016\/j.jaut.2019.102375","article-title":"Ebola virus disease: An emerging and re-emerging viral threat","volume":"106","author":"Rojas","year":"2020","journal-title":"J. Autoimmun."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.cytogfr.2026.01.008","article-title":"Cytokine storm divergence in viral infections of the upper respiratory tract","volume":"88","author":"Chen","year":"2026","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e2234","DOI":"10.1002\/rmv.2234","article-title":"Interindividual immunogenic variants: Susceptibility to coronavirus, respiratory syncytial virus and influenza virus","volume":"31","author":"Darbeheshti","year":"2021","journal-title":"Rev. Med. Virol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1111\/j.1365-2249.2004.02415.x","article-title":"Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome","volume":"136","author":"Wong","year":"2004","journal-title":"Clin. Exp. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1007\/s00281-017-0629-x","article-title":"Pathogenic human coronavirus infections: Causes and consequences of cyokine storm and immunopathology","volume":"39","author":"Channappanavar","year":"2017","journal-title":"Semin. Immunopathol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.cyto.2018.01.025","article-title":"MERS-CoV infection in humans is associated with a proinflammatory Th1 and Th17 cytokine profile","volume":"104","author":"Mahallawi","year":"2018","journal-title":"Cytokine"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/S0140-6736(20)30183-5","article-title":"Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China","volume":"395","author":"Huang","year":"2020","journal-title":"Lancet"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1016\/j.stem.2020.09.013","article-title":"SARS-CoV-2 Infection of Pluripotent Stem Cell-Derived Human Lung Alveolar Type 2 Cells Elicits a Rapid Epithelial-Intrinsic Inflammatory Response","volume":"27","author":"Huang","year":"2020","journal-title":"Cell Stem Cell"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1831","DOI":"10.1016\/S0140-6736(02)11772-7","article-title":"Induction of proinflammatory cytokines in human macrophages by influenza A (H5N1) virues: A mechanism for the unusual severity of human disease","volume":"360","author":"Cheung","year":"2002","journal-title":"Lancet"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.1038\/nm1477","article-title":"Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia","volume":"12","author":"Simmons","year":"2006","journal-title":"Nat. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1038\/nature05495","article-title":"Aberrant innate immune response in lethal infection of macaques with the 1918 influenza virus","volume":"445","author":"Kobasa","year":"2007","journal-title":"Nature"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"169","DOI":"10.4155\/fmc-2016-0181","article-title":"Current and future developments in the treatment of virus-induced hypercytokinemia","volume":"9","author":"Wong","year":"2017","journal-title":"Future Med. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","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":"ref_21","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1021\/acsinfecdis.6b00104","article-title":"Integration of Global Analyses of Host Molecular Responses with Clinical Data to Evaluate Pathogenesis and Advance Therapies for Emerging and Re-emerging Viral Infections","volume":"2","author":"Falcinelli","year":"2016","journal-title":"ACS Infect. Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.2353\/ajpath.2007.061088","article-title":"Pathology and Pathogenesis of Severe Acute Respiratory Syndrome","volume":"170","author":"Gu","year":"2007","journal-title":"Am. J. Pathol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Han, J.J., Song, H.A., Pierson, S.L., Shen-Gunther, J., and Xia, Q. (2023). Emerging Infectious Diseases Are Virulent Viruses\u2014Are We Prepared? An Overview. Microorganisms, 11.","DOI":"10.3390\/microorganisms11112618"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Khalaf, K., Papp, N., Chou, J.T.-T., Hana, D., Mackiewicz, A., and Kaczmarek, M. (2020). SARS-CoV-2: Pathogenesis, and Advancements in Diagnostics and Treatment. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.570927"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"115094","DOI":"10.1016\/j.diagmicrobio.2020.115094","article-title":"Clinical, molecular, and epidemiological characterization of the SARS-CoV-2 virus and the Coronavirus Disease 2019 (COVID-19), a comprehensive literature review","volume":"98","author":"Barreno","year":"2020","journal-title":"Diagn. Microbiol. Infect. Dis."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Speranza, E., and Connor, J.H. (2017). Host Transcriptional Response to Ebola Virus Infection. Vaccines, 5.","DOI":"10.3390\/vaccines5030030"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Zhang, Y.Y., Li, B.-R., and Ning, B.T. (2020). The Comparative Immunological Characteristics of SARS-CoV, MERS-CoV, and SARS-CoV-2 Coronavirus Infections. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.02033"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Kircheis, R., Haasbach, E., Lueftenegger, D., Heyken, W.T., Ocker, M., and Planz, O. (2020). NF-\u03baB Pathway as a Potential Target for Treatment of Critical Stage COVID-19 Patients. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.598444"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1016\/S0140-6736(21)00439-6","article-title":"Acute respiratory distress syndrome","volume":"398","author":"Meyer","year":"2021","journal-title":"Lancet"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e561","DOI":"10.1016\/j.lpm.2011.05.027","article-title":"Virus-induced acute respiratory distress syndrome: Epidemiology, management and outcome","volume":"40","author":"Luyt","year":"2011","journal-title":"Presse Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1016\/S0140-6736(22)01485-4","article-title":"Acute respiratory distress syndrome: Causes, pathophysiology, and phenotypes","volume":"400","author":"Bos","year":"2022","journal-title":"Lancet"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1055\/s-0039-1683996","article-title":"Pathogenesis of Acute Respiratory Distress Syndrome","volume":"40","author":"Huppert","year":"2019","journal-title":"Semin. Respir. Crit. Care Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2255","DOI":"10.1056\/NEJMra2026131","article-title":"Cytokine Storm","volume":"383","author":"Fajgenbaum","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"199306","DOI":"10.1016\/j.virusres.2023.199306","article-title":"Temporal cytokine storm dynamics in dengue infection predicts severity","volume":"341","author":"Bhatt","year":"2024","journal-title":"Virus Res."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Kircheis, R., and Planz, O. (2023). The Role of Toll-like Receptors (TLRs) and Their Related Signaling Pathways in Viral Infection and Inflammation. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24076701"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Olejnik, J., Hume, A.J., and M\u00fchlberger, E. (2018). Toll-like receptor 4 in acute viral infection: Too much of a good thing. PLoS Pathog., 14.","DOI":"10.1371\/journal.ppat.1007390"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/j.cell.2008.02.043","article-title":"Identification of oxidative stress and Toll-like receptor 4 signaling as a key pathway of acute lung injury","volume":"133","author":"Imai","year":"2008","journal-title":"Cell"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e12653","DOI":"10.1016\/j.heliyon.2022.e12653","article-title":"Association between the expression of toll-like receptors, cytokines, and homeostatic chemokines in SARS-CoV-2 infection and COVID-19 severity","volume":"9","author":"Alturaiki","year":"2023","journal-title":"Heliyon"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Halajian, E.A., LeBlanc, E.V., Gee, K., and Colpitts, C.C. (2022). Activation of TLR4 by viral glycoproteins: A double-edged sword?. Front. Microbiol., 13.","DOI":"10.3389\/fmicb.2022.1007081"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1080\/10409230802058320","article-title":"Structures and mechanisms of viral membrane fusion proteins: Multiple variations on a common theme","volume":"43","author":"White","year":"2008","journal-title":"Crit. Rev. Biochem. Mol. Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"8874339","DOI":"10.1155\/2021\/8874339","article-title":"COVID-19 and Toll-Like Receptor 4 (TLR4): SARS-CoV-2 May Bind and Activate TLR4 to Increase ACE2 Expression, Facilitating Entry and Causing Hyperinflammation","volume":"2021","author":"Aboudounya","year":"2021","journal-title":"Mediat. Inflamm."},{"key":"ref_42","doi-asserted-by":"crossref","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":"ref_43","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1038\/s41422-021-00495-9","article-title":"SARS-CoV-2 spike protein interacts with and activates TLR41","volume":"31","author":"Zhao","year":"2021","journal-title":"Cell Res."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Aboudounya, M.M., Holt, M.R., and Heads, R.J. (2021). SARS-CoV-2 Spike S1 glycoprotein is a TLR4 agonist, upregulates ACE2 expression and induces pro-inflammatory M1 macrophage polarisation. bioRxiv.","DOI":"10.1101\/2021.08.11.455921"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/j.cell.2020.02.052","article-title":"SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor","volume":"181","author":"Hoffmann","year":"2020","journal-title":"Cell"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Xia, X. (2021). Domains and Functions of Spike Protein in SARS-Cov-2 in the Context of Vaccine Design. Viruses, 13.","DOI":"10.3390\/v13010109"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Shah, M., and Woo, H.G. (2021). Omicron: A Heavily Mutated SARS-CoV-2 Variant Exhibits Stronger Binding to ACE2 and Potently Escapes Approved COVID-19 Therapeutic Antibodies. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.830527"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1038\/s41586-022-04441-6","article-title":"SARS-CoV-2 Omicron virus causes attenuated disease in mice and hamsters","volume":"603","author":"Halfmann","year":"2022","journal-title":"Nature"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1038\/s41586-022-04474-x","article-title":"Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts infectivity and fusogenicity","volume":"603","author":"Meng","year":"2022","journal-title":"Nature"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Korobova, Z.R., Arsentieva, N.A., Liubimova, N.E., Batsunov, O.K., Dedkov, V.G., Gladkikh, A.S., Sharova, A.A., Adish, Z., Chernykh, E.I., and Kaschenko, V.A. (2022). Cytokine Profiling in Different SARS-CoV-2 Genetic Variants. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232214146"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1007\/s10753-022-01734-w","article-title":"SARS-CoV-2 Variants Show a Gradual Declining Pathogenicity and Pro-Inflammatory Cytokine Stimulation, an Increasing Antigenic and Anti-Inflammatory Cytokine Induction, and Rising Structural Protein Instability: A Minimal Number Genome-Based Approach","volume":"46","author":"Barh","year":"2023","journal-title":"Inflammation"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1038\/s41586-022-04442-5","article-title":"Attenuated replication and pathogenicity of SARS-CoV-2 B.1.1.529 Omicron","volume":"603","author":"Shuai","year":"2022","journal-title":"Nature"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"e107821","DOI":"10.15252\/embj.2021107821","article-title":"TMPRSS2 expression dictates the entry route used by SARS-CoV-2 to infect host cells","volume":"40","author":"Koch","year":"2021","journal-title":"EMBO J."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Kircheis, R., and Planz, O. (2022). Could a Lower Toll-like Receptor (TLR) and NF-\u03baB Activation Due to a Changed Charge Distribution in the Spike Protein Be the Reason for the Lower Pathogenicity of Omicron?. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23115966"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2105","DOI":"10.1002\/jmv.25987","article-title":"In silico studies on the comparative characterization of the interactions of SARS-CoV-2 spike glycoprotein with ACE-2 receptor homologs and human TLRs","volume":"92","author":"Choudhury","year":"2020","journal-title":"J. Med. Virol."},{"key":"ref_56","doi-asserted-by":"crossref","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":"ref_57","doi-asserted-by":"crossref","unstructured":"Manavalan, B., Basith, S., and Choi, S. (2011). Similar Structures but Different Roles\u2014An Updated Perspective on TLR Structures. Front. Physiol., 2.","DOI":"10.3389\/fphys.2011.00041"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"e2210990119","DOI":"10.1073\/pnas.2210990119","article-title":"Nanomolar inhibition of SARS-CoV-2 infection by an unmodified peptide targeting the prehairpin intermediate of the spike protein","volume":"119","author":"Yang","year":"2022","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_59","doi-asserted-by":"crossref","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":"ref_60","doi-asserted-by":"crossref","first-page":"W365","DOI":"10.1093\/nar\/gkx407","article-title":"HDOCK: A web server for protein\u2013protein and protein\u2013DNA\/RNA docking based on a hybrid strategy","volume":"45","author":"Yan","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"e2119467119","DOI":"10.1073\/pnas.2119467119","article-title":"Structural conservation among variants of the SARS-CoV-2 spike postfusion bundle","volume":"119","author":"Yang","year":"2022","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"17958","DOI":"10.1073\/pnas.0406128102","article-title":"Structure of a proteolytically resistant core from the severe acute respiratory syndrome coronavirus S2 fusion protein","volume":"101","author":"Supekar","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1238","DOI":"10.1080\/22221751.2020.1770631","article-title":"Structural basis of HCoV-19 fusion core and an effective inhibition peptide against virus entry","volume":"9","author":"Sun","year":"2020","journal-title":"Emerg. Microbes Infect."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1627","DOI":"10.1021\/acschembio.5c00208","article-title":"SARS-CoV-2 Omicron Variant Spike Glycoprotein Mutation Q954H Enhances Fusion Core Stability","volume":"20","author":"Vithanage","year":"2025","journal-title":"ACS Chem. Biol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"e2300360120","DOI":"10.1073\/pnas.2300360120","article-title":"Structure-based design of a SARS-CoV-2 Omicron-specific inhibitor","volume":"120","author":"Yang","year":"2023","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"eaav4580","DOI":"10.1126\/sciadv.aav4580","article-title":"A pan-coronavirus fusion inhibitor targeting the HR1 domain of human coronavirus spike","volume":"5","author":"Xia","year":"2019","journal-title":"Sci. Adv."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2140","DOI":"10.1021\/jacs.9b11548","article-title":"Structure-guided improvement of a dual HPIV3\/RSV fusion inhibitor","volume":"142","author":"Outlaw","year":"2020","journal-title":"J. Am. Chem. Soc."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"2220","DOI":"10.1002\/prot.24585","article-title":"Influence of a heptad repeat stutter on the pH-dependent conformational behavior of the central coiled-coil from influenza hemagglutinin HA2","volume":"82","author":"Higgins","year":"2014","journal-title":"Proteins"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1021\/bi401525h","article-title":"Structural insights into the membrane fusion mechanism mediated by influenza virus hemagglutinin","volume":"53","author":"Ni","year":"2014","journal-title":"Biochemistry"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"109152","DOI":"10.1016\/j.celrep.2021.109152","article-title":"Snapshot of an influenza virus glycoprotein fusion intermediate","volume":"35","author":"Cook","year":"2021","journal-title":"Cell Rep."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1016\/j.cell.2015.12.044","article-title":"Ebola viral glycoprotein bound to its endosomal receptor Niemann-Pick C1","volume":"164","author":"Wang","year":"2016","journal-title":"Cell"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"e06187","DOI":"10.1016\/j.heliyon.2021.e06187","article-title":"SARS-CoV-2 spike protein S1 subunit induces pro-inflammatory responses via toll-like receptor 4 signaling in murine and human macrophages","volume":"7","author":"Shirato","year":"2021","journal-title":"Heliyon"},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Kircheis, R. (2024). In Silico Analyses Indicate a Lower Potency for Dimerization of TLR4\/MD-2 as the Reason for the Lower Pathogenicity of Omicron Compared to Wild-Type Virus and Earlier SARS-CoV-2 Variants. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25105451"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1038\/s41586-020-2180-5","article-title":"Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor","volume":"581","author":"Lan","year":"2020","journal-title":"Nature"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"e0012822","DOI":"10.1128\/jvi.00128-22","article-title":"Distinctive Roles of Furin and TMPRSS2 in SARS-CoV-2 Infectivity","volume":"96","author":"Essalmani","year":"2022","journal-title":"J. Virol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"12543","DOI":"10.1073\/pnas.0503203102","article-title":"Protease-mediated enhancement of severe acute respiratory syndrome coronavirus infection","volume":"102","author":"Matsuyama","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"11876","DOI":"10.1073\/pnas.0505577102","article-title":"Inhibitors of cathepsin L prevent severe acute respiratory syndrome coronavirus entry","volume":"102","author":"Simmons","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.3390\/v4061011","article-title":"Mechanisms of coronavirus cell entry mediated by the viral spike protein","volume":"4","author":"Belouzard","year":"2012","journal-title":"Viruses"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"408","DOI":"10.14348\/molcells.2021.0026","article-title":"Molecular Perspectives of SARS-CoV-2: Pathology, Immune Evasion, and Therapeutic Interventions","volume":"44","author":"Shah","year":"2021","journal-title":"Mol. Cells"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1007\/s00018-020-03656-y","article-title":"TLR4 and CD14 trafficking and its influence on LPS-induced pro-inflammatory signaling","volume":"78","author":"Ciesielska","year":"2021","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1038\/ni1569","article-title":"TRAM couples endocytosis of Toll-like receptor 4 to the induction of interferon-beta","volume":"9","author":"Kagan","year":"2008","journal-title":"Nat. Immunol."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Ahmed-Hassan, H., Sisson, B., Shukla, R.K., Wijewantha, Y., Funderburg, N.T., Li, Z., Hayes, D., Demberg, T., and Liyanage, N.P.M. (2020). Innate Immune Responses to Highly Pathogenic Coronaviruses and Other Significant Respiratory Viral Infections. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.01979"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1007\/s11239-020-02210-8","article-title":"COVID-19: Are we dealing with a multisystem vasculopathy in disguise of a viral infection?","volume":"50","author":"Mondal","year":"2020","journal-title":"J. Thromb. Thrombolysis"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"653110","DOI":"10.3389\/fimmu.2021.653110","article-title":"Endothelial Immunity Trained by Coronavirus Infections, DAMP Stimulations and Regulated by Anti-Oxidant NRF2 May Contribute to Inflammations, Myelopoiesis, COVID-19 Cytokine Storms and Thromboembolism","volume":"12","author":"Shao","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1052","DOI":"10.1016\/j.chom.2021.05.004","article-title":"Innate immune and inflammatory responses to SARS-CoV-2: Implications for COVID-19","volume":"29","author":"Lowery","year":"2021","journal-title":"Cell Host Microbe"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1007\/s00018-025-05631-x","article-title":"Role of TLRs as signaling cascades to combat infectious diseases: A review","volume":"82","author":"Salauddin","year":"2025","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.bjid.2015.10.011","article-title":"TLR2 and TLR4 mediated host immune responses in major infectious diseases: A review","volume":"20","author":"Mukherjee","year":"2016","journal-title":"Braz. J. Infect. Dis."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1038\/nrmicro1326","article-title":"Virus membrane-fusion proteins: More than one way to make a hairpin","volume":"4","author":"Kielian","year":"2006","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1038\/80833","article-title":"Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virus","volume":"1","author":"Popova","year":"2000","journal-title":"Nat. Immunol."},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Funchal, G.A., Jaeger, N., Czepielewski, R.S., Machado, M.S., Muraro, S.P., Stein, R.T., Bonorino, C.B., and Porto, B.N. (2015). Respiratory syncytial virus fusion protein promotes TLR-4-dependent neutrophil extracellular trap formation by human neutrophils. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0124082"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"10-128","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 (E5564) and requires direct interaction with MD-2","volume":"3","author":"Rallabhandi","year":"2012","journal-title":"mBio"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"e00179-17","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":"ref_93","doi-asserted-by":"crossref","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":"ref_94","doi-asserted-by":"crossref","unstructured":"Escudero-P\u00e9rez, B., Volchkova, V.A., Dolnik, O., Lawrence, P., and Volchkov, V.E. (2014). Shed GP of Ebola virus triggers immune activation and increased vascular permeability. PLoS Pathog., 10.","DOI":"10.1371\/journal.ppat.1004509"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"111562","DOI":"10.1016\/j.celrep.2022.111562","article-title":"Activation of Toll-like receptor 4 by Ebola virus-shed glycoprotein is direct and requires the internal fusion loop but not glycosylation","volume":"41","author":"Scherm","year":"2022","journal-title":"Cell Rep."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"R201","DOI":"10.1186\/cc8208","article-title":"Th1 and Th17 hypercytokinemia as early host response signature in severe pandemic influenza","volume":"13","author":"Pumarola","year":"2009","journal-title":"Crit. Care"},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Chen, B., Chen, C., Lu, F., Wang, X., Zhang, X., Wang, Z., and Liu, H. (2025). The Role of TLR4 in Lung Epithelial Cell Injury Caused by Influenza Virus Combined with Staphylococcus aureus. Microorganisms, 13.","DOI":"10.3390\/microorganisms13061201"},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Ferreira, A.C., Sacramento, C.Q., Pereira-Dutra, F.S., Fintelman-Rodrigues, N., Silva, P.P., Mattos, M., de Freitas, C.S., Marttorelli, A., de Melo, G.R., and Campos, M.M. (2023). Severe influenza infection is associated with inflammatory programmed cell death in infected macrophages. Front. Cell. Infect. Microbiol., 13.","DOI":"10.3389\/fcimb.2023.1067285"},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Wang, Q.W., Su, Y., Sheng, J.T., Gu, L.M., Zhao, Y., Chen, X.X., Chen, C., Li, W.Z., Li, K.S., and Dai, J.P. (2018). Anti-influenza A virus activity of rhein through regulating oxidative stress, TLR4, Akt, MAPK, and NF-\u03baB signal pathways. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0191793"},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Tsai, S.Y., Segovia, J.A., Chang, T.-H., Morris, I.R., Berton, M.T., Tessier, P.A., Tardif, M.R., Cesaro, A., and Bose, S. (2014). DAMP molecule S100A9 acts as a molecular pattern to enhance inflammation during influenza A virus infection: Role of DDX21-TRIF-TLR4-MyD88 pathway. PLoS Pathog., 10.","DOI":"10.1371\/journal.ppat.1003848"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1007\/s13238-015-0193-x","article-title":"Hemagglutinin-esterase-fusion (HEF) protein of influenza C. virus","volume":"7","author":"Wang","year":"2016","journal-title":"Protein Cell"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1007\/s12668-022-01020-x","article-title":"Mucosal Immunity After Novel COVID-19 Infection\u2013Virus-Induced Immunosuppression: Preliminary Study","volume":"12","author":"Agafonova","year":"2022","journal-title":"BioNanoScience"},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"Loftus, T.J., Ungaro, R., Dirain, M., Efron, P.A., Mazer, M.B., Remy, K.E., Hotchkiss, R.S., Zhong, L., Bacher, R., and Starostik, P. (2021). Overlapping but Disparate Inflammatory and Immunosuppressive Responses to SARS-CoV-2 and Bacterial Sepsis: An Immunological Time Course Analysis. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.792448"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"40611","DOI":"10.1074\/jbc.M112.404608","article-title":"Structural analyses of human Toll-like receptor 4 polymorphisms D299G and T399I","volume":"287","author":"Ohto","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1016\/j.virol.2005.02.022","article-title":"Central ions and lateral asparagine\/glutamine zippers stabilize the post-fusion hairpin conformation of the SARS coronavirus spike glycoprotein","volume":"335","author":"Duquerroy","year":"2005","journal-title":"Virology"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1829","DOI":"10.1038\/s41596-020-0312-x","article-title":"The HDOCK server for integrated protein\u2013protein docking","volume":"15","author":"Yan","year":"2020","journal-title":"Nat. Protoc."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1007\/978-1-0716-0708-4_12","article-title":"Modeling Protein-Protein or Protein-DNA\/RNA Complexes Using the HDOCK Webserver","volume":"2165","author":"Yan","year":"2020","journal-title":"Methods Mol. Biol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1002\/prot.25234","article-title":"Addressing recent docking challenges: A hybrid strategy to integrate template-based and free protein-protein docking","volume":"85","author":"Yan","year":"2017","journal-title":"Proteins"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"W431","DOI":"10.1093\/nar\/gkab314","article-title":"Mol* Viewer: Modern web app for 3D visualization and analysis of large biomolecular structures","volume":"49","author":"Sehnal","year":"2021","journal-title":"Nucleic Acids Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/12\/5317\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T07:04:05Z","timestamp":1781247845000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/12\/5317"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,12]]},"references-count":109,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["ijms27125317"],"URL":"https:\/\/doi.org\/10.3390\/ijms27125317","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,12]]}}}