{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T17:48:08Z","timestamp":1781286488261,"version":"3.54.1"},"reference-count":119,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2024,5,17]],"date-time":"2024-05-17T00:00:00Z","timestamp":1715904000000},"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 Omicron variants have replaced all earlier variants, due to increased infectivity and effective evasion from infection- and vaccination-induced neutralizing antibodies. Compared to earlier variants of concern (VoCs), the Omicron variants show high TMPRSS2-independent replication in the upper airway organs, but lower replication in the lungs and lower mortality rates. The shift in cellular tropism and towards lower pathogenicity of Omicron was hypothesized to correlate with a lower toll-like receptor (TLR) activation, although the underlying molecular mechanisms remained undefined. In silico analyses presented here indicate that the Omicron spike protein has a lower potency to induce dimerization of TLR4\/MD-2 compared to wild type virus despite a comparable binding activity to TLR4. A model illustrating the molecular consequences of the different potencies of the Omicron spike protein vs. wild-type spike protein for TLR4 activation is presented. Further analyses indicate a clear tendency for decreasing TLR4 dimerization potential during SARS-CoV-2 evolution via Alpha to Gamma to Delta to Omicron variants.<\/jats:p>","DOI":"10.3390\/ijms25105451","type":"journal-article","created":{"date-parts":[[2024,5,17]],"date-time":"2024-05-17T04:26:29Z","timestamp":1715919989000},"page":"5451","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["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"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4863-6705","authenticated-orcid":false,"given":"Ralf","family":"Kircheis","sequence":"first","affiliation":[{"name":"Syntacoll GmbH, 93342 Saal an der Donau, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1038\/s41586-022-04411-y","article-title":"Rapid epidemic expansion of the SARS-CoV-2 Omicron variant in southern Africa","volume":"603","author":"Viana","year":"2022","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1016\/S0140-6736(22)00017-4","article-title":"Early assessment of the clinical severity of the SARS-CoV-2 omicron variant in South Africa: A data linkage study","volume":"399","author":"Wolter","year":"2022","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1016\/j.cell.2021.12.046","article-title":"SARS-CoV-2 Omicron-B.1.1.529 leads to widespread escape from neutralizing antibody responses","volume":"185","author":"Dejnirattisai","year":"2022","journal-title":"Cell"},{"key":"ref_4","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_5","doi-asserted-by":"crossref","first-page":"102779","DOI":"10.1016\/j.jaut.2021.102779","article-title":"Omicron SARS-CoV-2 variant: Unique features and their impact on pre-existing antibodies","volume":"126","author":"Kannan","year":"2022","journal-title":"J. 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