The rs2228145 Variant of the Interleukin-6 Receptor (IL-6R) Gene Impacts on In Vitro Cellular Responses to SARS-CoV-2 VOC B1.1.7 Recombinant Spike Protein
Given the variability in inflammatory responses to SARS-CoV-2 infection observed within human populations, we aimed to develop an in vitro model system (based on monocyte-macrophages, a key relevant cell type) that could yield insights regarding the impact of rs2228145, a clinically relevant polymor...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-10-01
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| Series: | COVID |
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| Online Access: | https://www.mdpi.com/2673-8112/3/10/106 |
| _version_ | 1797574178718613504 |
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| author | Saira Sarwar Rebecca Aicheler Lee Butcher Katie Rees Stephen Potter Richard Rowlands Richard Webb |
| author_facet | Saira Sarwar Rebecca Aicheler Lee Butcher Katie Rees Stephen Potter Richard Rowlands Richard Webb |
| author_sort | Saira Sarwar |
| collection | DOAJ |
| description | Given the variability in inflammatory responses to SARS-CoV-2 infection observed within human populations, we aimed to develop an in vitro model system (based on monocyte-macrophages, a key relevant cell type) that could yield insights regarding the impact of rs2228145, a clinically relevant polymorphism within the coding region of a key inflammatory gene in the body’s response to SARS-CoV-2 infection: the interleukin-6 receptor (IL-6R) gene. Three monocyte-macrophage cell-lines (U937, THP-1, MM6) were shown to exhibit AA, AC and CC rs2228145 genotypes, respectively, and to exhibit an MM6 > THP-1 > U937 pattern regarding basal levels of soluble IL-6R (sIL-6R) release. Similar MM6 > THP-1 > U937 patterns were seen regarding the extents to which (i) circulating levels of the IL-6/sIL-6R ‘active complex’ increased and (ii) phosphorylation of the downstream transcription-factor STAT3 occurred, following treatment with SARS-CoV-2 spike protein (SP). Moreover, a blocking antibody for the ACE-2 entry receptor for SARS-CoV-2 suppressed effects (i) and (ii), suggesting that interaction between SP and ACE-2 is the initial event that triggers IL-6/IL-6R signalling in our system. Production of IL-8 occurred to greater extents in A549 lung epithelial cells treated with tissue-culture supernatants from SP-treated MM6 cultures than SP-treated THP-1 or U937 cultures. Our data indicate that the rs2228145 genotype significantly impacts upon SP-associated IL-6/sIL-6R signalling in vitro, suggesting that it may influence in vivo risk of developing severe COVID-19 and/or long-COVID symptoms following infection by SARS-CoV-2. Thus, the rs2228145 genotype may have potential as a biomarker that differentiates between patients at risk of developing severe and/or prolonged symptoms following infection by SARS-CoV-2 and those who are at less risk. |
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| institution | Directory Open Access Journal |
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| language | English |
| last_indexed | 2024-03-10T21:19:10Z |
| publishDate | 2023-10-01 |
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| record_format | Article |
| series | COVID |
| spelling | doaj.art-02991811ef5a4ef8999c2e618d36824e2023-11-19T16:08:42ZengMDPI AGCOVID2673-81122023-10-013101554157010.3390/covid3100106The rs2228145 Variant of the Interleukin-6 Receptor (IL-6R) Gene Impacts on In Vitro Cellular Responses to SARS-CoV-2 VOC B1.1.7 Recombinant Spike ProteinSaira Sarwar0Rebecca Aicheler1Lee Butcher2Katie Rees3Stephen Potter4Richard Rowlands5Richard Webb6Department of Biomedical Sciences, School of Sport and Health Sciences, Cardiff Metropolitan University, Cardiff CF5 2YB, UKDepartment of Biomedical Sciences, School of Sport and Health Sciences, Cardiff Metropolitan University, Cardiff CF5 2YB, UKDepartment of Biomedical Sciences, School of Sport and Health Sciences, Cardiff Metropolitan University, Cardiff CF5 2YB, UKDepartment of Biomedical Sciences, School of Sport and Health Sciences, Cardiff Metropolitan University, Cardiff CF5 2YB, UKDepartment of Biomedical Sciences, School of Sport and Health Sciences, Cardiff Metropolitan University, Cardiff CF5 2YB, UKDepartment of Biomedical Sciences, School of Sport and Health Sciences, Cardiff Metropolitan University, Cardiff CF5 2YB, UKDepartment of Biomedical Sciences, School of Sport and Health Sciences, Cardiff Metropolitan University, Cardiff CF5 2YB, UKGiven the variability in inflammatory responses to SARS-CoV-2 infection observed within human populations, we aimed to develop an in vitro model system (based on monocyte-macrophages, a key relevant cell type) that could yield insights regarding the impact of rs2228145, a clinically relevant polymorphism within the coding region of a key inflammatory gene in the body’s response to SARS-CoV-2 infection: the interleukin-6 receptor (IL-6R) gene. Three monocyte-macrophage cell-lines (U937, THP-1, MM6) were shown to exhibit AA, AC and CC rs2228145 genotypes, respectively, and to exhibit an MM6 > THP-1 > U937 pattern regarding basal levels of soluble IL-6R (sIL-6R) release. Similar MM6 > THP-1 > U937 patterns were seen regarding the extents to which (i) circulating levels of the IL-6/sIL-6R ‘active complex’ increased and (ii) phosphorylation of the downstream transcription-factor STAT3 occurred, following treatment with SARS-CoV-2 spike protein (SP). Moreover, a blocking antibody for the ACE-2 entry receptor for SARS-CoV-2 suppressed effects (i) and (ii), suggesting that interaction between SP and ACE-2 is the initial event that triggers IL-6/IL-6R signalling in our system. Production of IL-8 occurred to greater extents in A549 lung epithelial cells treated with tissue-culture supernatants from SP-treated MM6 cultures than SP-treated THP-1 or U937 cultures. Our data indicate that the rs2228145 genotype significantly impacts upon SP-associated IL-6/sIL-6R signalling in vitro, suggesting that it may influence in vivo risk of developing severe COVID-19 and/or long-COVID symptoms following infection by SARS-CoV-2. Thus, the rs2228145 genotype may have potential as a biomarker that differentiates between patients at risk of developing severe and/or prolonged symptoms following infection by SARS-CoV-2 and those who are at less risk.https://www.mdpi.com/2673-8112/3/10/106IL-6sIL-6RCOVID-19long-COVIDmonocyte-macrophagegenetic variants |
| spellingShingle | Saira Sarwar Rebecca Aicheler Lee Butcher Katie Rees Stephen Potter Richard Rowlands Richard Webb The rs2228145 Variant of the Interleukin-6 Receptor (IL-6R) Gene Impacts on In Vitro Cellular Responses to SARS-CoV-2 VOC B1.1.7 Recombinant Spike Protein COVID IL-6 sIL-6R COVID-19 long-COVID monocyte-macrophage genetic variants |
| title | The rs2228145 Variant of the Interleukin-6 Receptor (IL-6R) Gene Impacts on In Vitro Cellular Responses to SARS-CoV-2 VOC B1.1.7 Recombinant Spike Protein |
| title_full | The rs2228145 Variant of the Interleukin-6 Receptor (IL-6R) Gene Impacts on In Vitro Cellular Responses to SARS-CoV-2 VOC B1.1.7 Recombinant Spike Protein |
| title_fullStr | The rs2228145 Variant of the Interleukin-6 Receptor (IL-6R) Gene Impacts on In Vitro Cellular Responses to SARS-CoV-2 VOC B1.1.7 Recombinant Spike Protein |
| title_full_unstemmed | The rs2228145 Variant of the Interleukin-6 Receptor (IL-6R) Gene Impacts on In Vitro Cellular Responses to SARS-CoV-2 VOC B1.1.7 Recombinant Spike Protein |
| title_short | The rs2228145 Variant of the Interleukin-6 Receptor (IL-6R) Gene Impacts on In Vitro Cellular Responses to SARS-CoV-2 VOC B1.1.7 Recombinant Spike Protein |
| title_sort | rs2228145 variant of the interleukin 6 receptor il 6r gene impacts on in vitro cellular responses to sars cov 2 voc b1 1 7 recombinant spike protein |
| topic | IL-6 sIL-6R COVID-19 long-COVID monocyte-macrophage genetic variants |
| url | https://www.mdpi.com/2673-8112/3/10/106 |
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