tetano
Editor, Senior Moderator
Mol Biol Rep
. 2025 Jun 23;52(1):629.
doi: 10.1007/s11033-025-10736-4. The monomeric but not homotrimeric spike protein of SARS-CoV-2 activates TLR4 signaling
Charlotte Lübow[SUP] 1 [/SUP], Günther Weindl[SUP] 2 [/SUP]
Affiliations
Background: Recent findings indicate that hyperinflammatory responses to SARS-CoV-2 are major contributors to the severity and fatality of COVID-19. Pattern recognition receptors, particularly Toll-like receptors 2 (TLR2) and 4 (TLR4), have been implicated in detecting SARS-CoV-2 proteins, especially the spike protein. However, the role of viral structural components in triggering innate immune responses remains poorly understood.
Methods and results: HEK293 reporter cells, engineered to stably express TLR2 or TLR4, and THP-1 differentiated macrophages were exposed to various spike protein components and SARS-CoV-2 variants. Protein levels of cytokines were detected by ELISA and mRNA expression was evaluated by quantitative real-time RT-PCR. We demonstrate that the S1 subunit and full-length spike protein elicit TLR4-dependent pro-inflammatory responses. TLR4 activation was triggered by the monomeric, but not the homotrimeric, form of the SARS-CoV-2 spike protein.
Conclusions: These findings suggest that distinct elements of the SARS-CoV-2 spike protein differentially activate TLR4 signaling pathways, driving innate immune and inflammatory responses.
Keywords: COVID-19 pathogenesis; Innate immunity; Pro-inflammatory response; SARS-CoV-2 Spike protein; TLR4 signaling.
. 2025 Jun 23;52(1):629.
doi: 10.1007/s11033-025-10736-4. The monomeric but not homotrimeric spike protein of SARS-CoV-2 activates TLR4 signaling
Charlotte Lübow[SUP] 1 [/SUP], Günther Weindl[SUP] 2 [/SUP]
Affiliations
- PMID: 40549076
- PMCID: PMC12185570
- DOI: 10.1007/s11033-025-10736-4
Background: Recent findings indicate that hyperinflammatory responses to SARS-CoV-2 are major contributors to the severity and fatality of COVID-19. Pattern recognition receptors, particularly Toll-like receptors 2 (TLR2) and 4 (TLR4), have been implicated in detecting SARS-CoV-2 proteins, especially the spike protein. However, the role of viral structural components in triggering innate immune responses remains poorly understood.
Methods and results: HEK293 reporter cells, engineered to stably express TLR2 or TLR4, and THP-1 differentiated macrophages were exposed to various spike protein components and SARS-CoV-2 variants. Protein levels of cytokines were detected by ELISA and mRNA expression was evaluated by quantitative real-time RT-PCR. We demonstrate that the S1 subunit and full-length spike protein elicit TLR4-dependent pro-inflammatory responses. TLR4 activation was triggered by the monomeric, but not the homotrimeric, form of the SARS-CoV-2 spike protein.
Conclusions: These findings suggest that distinct elements of the SARS-CoV-2 spike protein differentially activate TLR4 signaling pathways, driving innate immune and inflammatory responses.
Keywords: COVID-19 pathogenesis; Innate immunity; Pro-inflammatory response; SARS-CoV-2 Spike protein; TLR4 signaling.