{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T14:43:08Z","timestamp":1779201788702,"version":"3.51.4"},"reference-count":256,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T00:00:00Z","timestamp":1759795200000},"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. Immunol."],"abstract":"<jats:p>Innate immunity is the first line of defense against infections, including the detection and response to SARS-CoV-2. Cells of the innate system are usually activated within hours after pathogen exposure and do not generate conventional immunological memory. In this review, the current knowledge of the innate immune cells and of pattern-recognition receptors in sensing and responding to SARS-CoV-2 to mount a protective response has been shortly reviewed. Subsequently, the evasion strategies of the virus, as the inhibition of IFN-I\/III production and autophagic response, counteracting the innate cell activity (including NK cells), have been briefly outlined. In the course of the infection, these strategies are also capable of rendering dysfunctional most innate cells, thus deeply interfering with the onset and maintenance of adaptive immunity. Possible mechanism(s) for the maintenance of dysfunctional innate immune response are also discussed. In this context, the importance of a rapid and robust activation of innate immunity through toll-like receptor (TLR) 4 as a key paradigm central to host defense against COVID-19 pathogenesis is also illustrated. We also discuss how the viral excess plus inflammatory signals upregulating TLR4 on innate cells may initiate a vicious loop which maintains and improves hyperinflammation, leading to the most critical outcomes. Targeting the TLR4 or its signaling pathway may be a promising therapeutic strategy, offering the dual benefits of viral suppression and decreasing inflammation.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1658396","type":"journal-article","created":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T05:35:00Z","timestamp":1759815300000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["The innate immune response in SARS-CoV2 infection: focus on toll-like receptor 4 in severe disease outcomes"],"prefix":"10.3389","volume":"16","author":[{"given":"Enrico","family":"Maggi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nadine","family":"Landolina","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesca Romana","family":"Mariotti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Enrico","family":"Munari","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicola","family":"Tumino","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paola","family":"Vacca","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bruno","family":"Azzarone","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lorenzo","family":"Moretta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,10,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1111\/apm.13109","article-title":"On the history of human coronaviruses","volume":"129","author":"Kronvall","year":"2021","journal-title":"APMIS"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2008-3","article-title":"A new coronavirus associated with human respiratory disease in China","volume":"579","author":"Wu","year":"2020","journal-title":"Nature"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.jinf.2020.03.037","article-title":"The pathogenesis and treatment of the;Cytokine Storm\u2019 in COVID-19","volume":"80","author":"Ye","year":"2020","journal-title":"J Infect"},{"key":"B4","doi-asserted-by":"publisher","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":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-020-1051-9","article-title":"An inflammatory cytokine signature predicts COVID-19 severity and survival","volume":"26","author":"Del Valle","year":"2020","journal-title":"Nat Med"},{"key":"B6","doi-asserted-by":"publisher","first-page":"681","DOI":"10.1016\/j.it.2021.06.001","article-title":"The \u2018cytokine storm\u2019: molecular mechanisms and therapeutic prospects","volume":"42","author":"Karki","year":"2021","journal-title":"Trends Immunol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1147476","article-title":"Trained immunity: A \u201cnew\u201d weapon in the fight against infectious diseases","volume":"14","author":"Dagenais","year":"2023","journal-title":"Front Immunol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"3917","DOI":"10.1038\/s41467-021-22785-x","article-title":"The architecture of the SARS-CoV-2 RNA genome inside virion","volume":"12","author":"Cao","year":"2021","journal-title":"Nat Commun"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3390\/v13020243","article-title":"Evolution of SARS-coV-2 envelope, membrane, nucleocapsid, and spike structural proteins from the beginning of the pandemic to september 2020: A global and regional approach by epidemiological week","volume":"13","author":"Troyano-Hernaez","year":"2021","journal-title":"Viruses"},{"key":"B10","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1038\/s41580-021-00418-x","article-title":"Mechanisms of SARS-CoV-2 entry into cells","volume":"23","author":"Jackson","year":"2022","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"779","DOI":"10.1016\/j.molcel.2020.04.022","article-title":"A multibasic cleavage site in the spike protein of SARS-coV-2 is essential for infection of human lung cells","volume":"78","author":"Hoffmann","year":"2020","journal-title":"Mol Cell"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3390\/vaccines11020204","article-title":"S protein, ACE2 and host cell proteases in SARS-coV-2 cell entry and infectivity; is soluble ACE2 a two blade sword? 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