{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:47:58Z","timestamp":1787028478283,"version":"build-2736575974"},"reference-count":193,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2022,5,25]],"date-time":"2022-05-25T00:00:00Z","timestamp":1653436800000},"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 novel SARS-CoV-2 Omicron variant B.1.1.529, which emerged in late 2021, is currently active worldwide, replacing other variants, including the Delta variant, due to an enormously increased infectivity. Multiple substitutions and deletions in the N-terminal domain (NTD) and the receptor binding domain (RBD) in the spike protein collaborate with the observed increased infectivity and evasion from therapeutic monoclonal antibodies and vaccine-induced neutralizing antibodies after primary\/secondary immunization. In contrast, although three mutations near the S1\/S2 furin cleavage site were predicted to favor cleavage, observed cleavage efficacy is substantially lower than in the Delta variant and also lower compared to the wild-type virus correlating with significantly lower TMPRSS2-dependent replication in the lungs, and lower cellular syncytium formation. In contrast, the Omicron variant shows high TMPRSS2-independent replication in the upper airway organs, but lower pathogenicity in animal studies and clinics. Based on recent data, we present here a hypothesis proposing that the changed charge distribution in the Omicron\u2019s spike protein could lead to lower activation of Toll-like receptors (TLRs) in innate immune cells, resulting in lower NF-\u03baB activation, furin expression, and viral replication in the lungs, and lower immune hyper-activation.<\/jats:p>","DOI":"10.3390\/ijms23115966","type":"journal-article","created":{"date-parts":[[2022,5,26]],"date-time":"2022-05-26T08:50:22Z","timestamp":1653555022000},"page":"5966","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["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?"],"prefix":"10.3390","volume":"23","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"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3701-943X","authenticated-orcid":false,"given":"Oliver","family":"Planz","sequence":"additional","affiliation":[{"name":"Interfaculty Institute for Cell Biology, Department of Immunology, Eberhard Karls University Tuebingen, 72076 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,25]]},"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":"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_3","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_4","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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