SARS-CoV-2 spike protein binds to bacterial lipopolysaccharide and boosts proinflammatory activity

Awoyemi et al., 2018) as well as obesitynHighlight:metabolic syndrome are at risk of developing severe COVID-19 disease and ARDSnHighlight:SARS-CoV-2 S protein binds to LPSnHighlight:The protein also boosted inflammatory responses when combined with low levels of LPSnHighlight:In nuclear factor-kappa B (NF-κB) reporter mice, SARS-CoV-2 S protein significantly increased the inflammatory response in conjunction with ultra-low, threshold levels of LPSnHighlight:specific binding of LPS to SARS-CoV-2 S protein was identifiednHighlight:affinity of LPS to SARS-CoV-2 S proteinnHighlight:Moreover, the related SARS-CoV S protein also bound to LPSnHighlight:LPS effects depend on specific interactions with components of innate immunity such as LPS-binding protein (LBP), culminating in transfer of LPS from CD14 to toll-like receptor 4 (TLR4)nHighlight:leading to activation of downstream inflammatory responsesnHighlight:Addition of S protein at increasing concentrations resulted in a gradual and significant increase in NF-κB/AP-1 activationnHighlight:SARS-CoV-2 S protein alone did not induce any significant increase in NF-κB/AP-1 activationnHighlight:NF-κB activation was significantly boosted even at those low doses of LPSnHighlight:It was also observed that LPS at doses of 0.5–1 ng/ml, combined with SARS-CoV-2 S protein, yielded response levels produced by 10 ng/ml LPSnHighlight:ultra-low levels of LPS and SARS-CoV-2 S protein yielded significant boosting of TNF-α and interleukin-6 (IL-6)nHighlight:NF-κB activation, thus representing the proximal LPS-dependent cytokine responsenHighlight:activation by low/threshold levels of LPS is boosted several-fold by the addition of SARS-CoV-2 S proteinnHighlight:strongly increased response by the LPS and SARS-CoV-2 S protein combinationnHighlight:endotoxin-driven inflammationnHighlight:SARS-CoV-2 S protein alone at the dose of 5 µg did not yield any significant inflammatory responsenHighlight:LPS‒S protein mix resulted in a prolonged NF-κB responsenHighlight:SARS-CoV-2 S protein both binds to and boosts LPS responsesnHighlight:SARS-CoV-2 S protein induced a marked disaggregation of LPS at subnanomolar to nanomolar levelsnHighlight:interaction between SARS-CoV-2 S protein and LPS, leading to a boosting of proinflammatory actions in vitro as well as in vivonHighlight:synergism between LPS and S protein have clinical and therapeutic importancenHighlight:S protein and LPSnHighlight:leading to changes in the biophysical state of LPSnHighlight:Complex and sequential interactions between LPS and LBP aid in LPS transfer to CD14 and subsequent downstream NF-κB activation nHighlight:disaggregation of LPS by LPB as well as other proteins has been reported to boost LPS proinflammatory effectsnHighlight:Proposed proinflammatory mechanism of SARS-CoV-2 S protein. In the absence of S protein, LPS micelles are present. At low S protein concentrations, some LPS molecules bind to S protein resulting in disaggregation of the LPS aggregates. Free LPS molecules are then able to bind to the LPS receptor, CD14, before being transferred to the TLR4/MD2 complex, which activates downstream signaling. At high S protein concentrations, most LPS molecules are bound to the S protein, and the S protein‒LPS complex then forms large aggregates [modelled based on S protein dimer of trimers ()], which may promote inflammatory responsesnSticky notes:Double Whammy!!nHighlight:pathogenetic link to SARS-CoV-2 infection and endotoxinemianHighlight:pathogenetic link to SARS-CoV-2 infection and endotoxinemianHighlight:periodontitisnHighlight:measurement of endotoxin levels in COVID-19 patients could have significant diagnostic implications and be of relevance for patient management and treatment decisionsnHighlight:interaction between the SARS-CoV-2 S protein and LPS and its link to induction of NF-κB and cytokine responses in monocytes, PBMCs, and human blood, as well as increased NF-κB responses in experimental animal modelsnHighlight:The interaction between S protein and LPS therefore provides a new therapeutic target enabling development of drugs that can ameliorate the hyperinflammation seen during COVID-19 infectionnSticky notes:Oh good grief!n]]>

Picture of About Dr. Nathan Goodyear
About Dr. Nathan Goodyear

Dr. Nathan Goodyear, a medical doctor with years of experience in the field of integrative cancer care, has announced the launch of an online training program. This program, available on his new website, will provide individuals with access to video trainings led by Dr. Goodyear himself, covering a range of topics related to integrative cancer care. These trainings will include information on the latest research and techniques in the field, as well as guidance on how to incorporate these approaches into a patient’s overall cancer treatment plan. With this online program, Dr. Goodyear hopes to make his expertise and knowledge more widely accessible, and help more people understand the benefits of integrative cancer care.

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