AUTHOR=Maggi Enrico , Landolina Nadine , Mariotti Francesca Romana , Munari Enrico , Tumino Nicola , Vacca Paola , Azzarone Bruno , Moretta Lorenzo 

TITLE=The innate immune response in SARS-CoV2 infection: focus on toll-like receptor 4 in severe disease outcomes

JOURNAL=Frontiers in Immunology

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1658396

DOI=10.3389/fimmu.2025.1658396

ISSN=1664-3224

ABSTRACT=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.