Induction of Exaggerated Cytokine Production in Human Peripheral Blood Mononuclear Cells by a Recombinant SARS-CoV-2 Spike Glycoprotein S1 and Its Inhibition by Dexamethasone

Olajide, Olumayokun A.; Iwuanyanwu, Victoria U; Lepiarz-Raba, Izabela; Al-Hindawi, Alaa A

doi:10.1007/s10753-021-01464-5

Cited by 48 publications

(50 citation statements)

References 47 publications

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“…With respect to immune responses induced by SARS-CoV-2 infection, it is now established that this may involve an exaggerated inflammation, also known as cytokine storm [33-35]. Recently, we reported induction of increased release of pro-inflammatory cytokines in human peripheral blood mononuclear cells stimulated with a recombinant SARS-CoV-2 spike protein sub-unit S1, further confirming the role of the spike protein in COVID-19 cytokine storm [36].…”

Section: Discussionmentioning

confidence: 71%

SARS-CoV-2 spike glycoprotein S1 induces neuroinflammation in BV-2 microglia

Olajide

Iwuanyanwu

Adegbola

2020

Preprint

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The emergence of SARS‐CoV‐2 has resulted in a global pandemic. In addition to respiratory complications as a result of SARS‐CoV‐2 illness, accumulating evidence suggests that neurological and neuropsychiatric symptoms are associated with the disease caused by the virus. In this study, we investigated the effects of the SARS‐CoV‐2 spike glycoprotein S1 stimulation on neuroinflammation in BV-2 microglia. Analyses of culture supernatants revealed an increase in the production of TNFα, IL-6, IL-1β and iNOS/NO. SARS‐CoV‐2 spike glycoprotein S1 increased protein expressions of phospho-p65 and phospho-IκB, as well as enhancing DNA binding and transcriptional activity of NF-κB. Pro-inflammatory effects of the glycoprotein effects were reduced in the presence of BAY11-7082 (1 μM). The presence of SARS‐CoV‐2 spike glycoprotein S1 in BV-2 microglia increased the protein expression of NLRP3, as well as caspase-1 activity. However, pre-treatment with CRID3 (1 μM) or BAY11-7082 (1 μM) resulted in the inhibition of NLRP3 inflammasome/caspase-1. It was also observed that CRID3 attenuated SARS‐CoV‐2 spike glycoprotein S1-induced increase in IL-1β production. Increased protein expression of p38 MAPK was observed in BV-2 microglia stimulated with the spike glycoprotein S1, and was reduced in the presence of SKF 86002. These results have provided the first evidence demonstrating SARS-CoV-2 spike S1 glycoprotein-induced neuroinflammation in BV-2 microglia. We propose that promotion of neuroinflammation by this glycoprotein is mediated through activation of NF-κB, NLRP3 inflammasome and p38 MAPK. These results are significant because of their relevance to our understanding of neurological and neuropsychiatric symptoms observed in patients infected with SARS-CoV-2.

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Section: Discussionmentioning

confidence: 71%

SARS-CoV-2 spike glycoprotein S1 induces neuroinflammation in BV-2 microglia

Olajide

Iwuanyanwu

Adegbola

2020

Preprint

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“…Finally, we tested 3 investigational therapies previously predicted as potentially effective in SARS-CoV-2 infection, including sirolimus ( 25 , 26 ), metformin ( 27 – 29 ), and β-D-N 4 -hydroxycytidine (N-hydroxycytidine) ( 30 ). We found that sirolimus was highly effective in reducing virus titer in tissues from 3 donors but did not significantly affect titers in 2 donors or Vero cells ( Figure 4D ).…”

Section: Resultsmentioning

confidence: 99%

“…Dexamethasone is a corticosteroid and proven therapy for SARS-CoV-2 infection ( 22 , 23 ). The mechanism of action of dexamethasone that improves the outcome of SARS-CoV-2 infection is not empirically established but is thought to be attenuation of inflammation ( 24 , 25 ).…”

Section: Resultsmentioning

confidence: 99%

Ex vivo SARS-CoV-2 infection of human lung reveals heterogeneous host defense and therapeutic responses

Schaller¹,

Sharma²,

Dupee³

et al. 2021

JCI Insight

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Cell lines are the mainstay in understanding the biology of COVID-19 infection but do not recapitulate many of the complexities of human infection. The use of human lung tissue is one solution for the study of such novel respiratory pathogens. We hypothesized that a cryopreserved bank of human lung tissue would allow for the ex vivo study of the interindividual heterogeneity of host response to SARS-CoV-2, thus providing a bridge between studies with cell lines and studies in animal models. We generated a cryobank of tissues from 21 donors, many of whom had clinical risk factors for severe COVID-19. Cryopreserved tissues preserved 90% cell viability and contained heterogenous populations of metabolically active epithelial, endothelial, and immune cell subsets of the human lung. Samples were readily infected with HCoV-OC43 and SARS-CoV-2 and demonstrated comparable susceptibility to infection. In contrast, we observed a marked donor-dependent heterogeneity in the expression of IL6 , CXCL8 , and IFNB1 in response to SARS-CoV-2. Treatment of tissues with dexamethasone and the experimental drug N-hydroxycytidine suppressed viral growth in all samples, whereas chloroquine and remdesivir had no detectable effect. Metformin and sirolimus, molecules with predicted but unproven antiviral activity, each suppressed viral replication in tissues from a subset of donors. In summary, we developed a system for the ex vivo study of human SARS-CoV-2 infection using primary human lung tissue from a library of donor tissues. This model may be useful for drug screening and for understanding basic mechanisms of COVID-19 pathogenesis.

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“…Furthermore, a review by Hariharan et al (2021) suggests that inhibition of NF-B activation, with the resultant reduction in exaggerated production of pro-inflammatory cytokines like TNF will potentially result in a reduction in cytokine storm in severe COVID-19. Our recent studies also showed that NF-B activation is a mechanism for SARS-CoV-2 spike protein S1-induced exaggerated production of TNF, IL-6, IL-1β and IL-8 in PBMCs (Olajide et al, 2021). The seed extract of Garcinia kola and garcinoic acid inhibited both cytoplasmic activation, DNA binding and transcriptional activity of NF-B in SARS-CoV-2 spike protein S1-simulated PBMCs, suggesting a role for the transcription factor in their anti-inflammatory activities.…”

Section: Discussionmentioning

confidence: 65%

“…Interestingly, studies have shown that the spike glycoproteins, especially the S1 sub-unit are also a target for the host immune responses (Merad et al, 2020). Recent studies have confirmed that the S1 sub-unit induced inflammation in immune cells through activation of cellular inflammatory signalling pathways (Shirato and Kizaki, 2021;Olajide et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

Garcinia kola and garcinoic acid suppress SARS-CoV-2 spike glycoprotein S1-induced hyper-inflammation in human PBMCs through inhibition of NF-κB activation

Olajide

Iwuanyanwu

Lepairz-Raba

et al. 2021

Preprint

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Symptoms and complications associated with severe SARS-CoV-2 infection such as acute respiratory distress syndrome (ARDS) and organ damage have been linked to SARS-CoV-2 spike glycoprotein S1-induced increased production of pro inflammatory cytokines by immune cells. In this study, the effects of an extract of Garcinia kola seeds and garcinoic acid were investigated in SARS-CoV-2 spike glycoprotein S1-stimulated human PBMCs. Results of ELISA experiments revealed that Garcinia kola extract (6.25, 12.5 and 25 μg/mL) and garcinoic acid (1.25, 2.5 and 5 μM) significantly reduced SARS-CoV-2 spike glycoprotein S1-induced increased secretion of TNFα, IL-6, IL-1β and IL-8 in PBMCs. In-cell western assays showed that pre-treatment with Garcinia kola extract and garcinoic acid reduced elevated expressions of both phospho-p65 and phospho-IκBα proteins, as well as NF-κB DNA binding capacity and NF-κB driven luciferase expression following stimulation of PBMCs with spike glycoprotein S1. Furthermore, pre-treatment of PBMCs with Garcinia kola extract prior to stimulation with SARS-CoV-2 spike glycoprotein S1 resulted in reduced damage to adjacent A549 lung epithelial cells. Gas Chromatography-Mass Spectrometry (GCMS) and HPLC-PDA confirmed the presence of garcinoic acid in the Garcinia kola extract used in this study. These results suggest that the seed of Garcinia kola and garcinoic acid are natural products which may possess pharmacological/therapeutic benefits in reducing cytokine storm during the late stage of severe SARS-CoV-2 and other coronavirus infections.

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Induction of Exaggerated Cytokine Production in Human Peripheral Blood Mononuclear Cells by a Recombinant SARS-CoV-2 Spike Glycoprotein S1 and Its Inhibition by Dexamethasone

Cited by 48 publications

References 47 publications

SARS-CoV-2 spike glycoprotein S1 induces neuroinflammation in BV-2 microglia

SARS-CoV-2 spike glycoprotein S1 induces neuroinflammation in BV-2 microglia

Ex vivo SARS-CoV-2 infection of human lung reveals heterogeneous host defense and therapeutic responses

Garcinia kola and garcinoic acid suppress SARS-CoV-2 spike glycoprotein S1-induced hyper-inflammation in human PBMCs through inhibition of NF-κB activation

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