A Hybrid Soluble gp130/Spike-Nanobody Fusion Protein Simultaneously Blocks Interleukin-6 trans -Signaling and Cellular Infection with SARS-CoV-2
| العنوان: | A Hybrid Soluble gp130/Spike-Nanobody Fusion Protein Simultaneously Blocks Interleukin-6 trans -Signaling and Cellular Infection with SARS-CoV-2 |
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| المؤلفون: | Julia Ettich, Julia Werner, Hendrik T. Weitz, Eva Mueller, Roland Schwarzer, Philipp A. Lang, Jürgen Scheller, Jens M. Moll |
| المصدر: | Journal of Virology. 96 |
| بيانات النشر: | American Society for Microbiology, 2022. |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | Virology, Insect Science, Immunology, Medizin, Microbiology |
| الوصف: | Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can induce mild to life-threatening symptoms. Especially individuals over 60 years of age or with underlying comorbidities, including heart or lung disease and diabetes, or immunocompromised patients are at a higher risk. Fatal multiorgan damage in coronavirus disease 2019 (COVID-19) patients can be attributed to an interleukin-6 body treatment for severe COVID-19 cases has been approved for therapy. High concentrations of soluble IL-6R (sIL-6R) were found in COVID-19 intensive care unit patients, suggesting the involvement of IL-6 trans-signaling in disease pathology. Here, in analogy to bispecific antibodies (bsAbs), we developed the first bispecific IL-6 trans-signaling inhibitor, c19s130Fc, which blocks viral infection and IL-6 trans-signaling. c19s130Fc is a designer protein of the IL-6 trans-signaling inhibitor cs130 fused to a single-domain nanobody directed against the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. c19s130Fc binds with high affinity to IL-6:sIL-6R complexes as well as the spike protein of SARS-CoV-2, as shown by surface plasmon resonance. Using cell-based assays, we demonstrate that c19s130Fc blocks IL-6 trans-signaling-induced proliferation and STAT3 phosphorylation in Ba/F3-gp130 cells as well as SARS-CoV-2 infection and STAT3 phosphorylation in Vero cells. Taken together, c19s130Fc represents a new class of bispecific inhibitors consisting of a soluble cytokine receptor fused to antiviral nanobodies and principally demonstrates the multifunctionalization of trans-signaling inhibitors. IMPORTANCE The availability of effective SARS-CoV-2 vaccines is a large step forward in managing the pandemic situation. In addition, therapeutic options, e.g., monoclonal antibodies to prevent viral cell entry and anti-inflammatory therapies, including glucocorticoid treatment, are currently developed or in clinical use to treat already infected patients. Here, we report a novel dual-specificity inhibitor to simultaneously target SARS-CoV-2 infection and virus-induced hyperinflammation. This was achieved by fusing an inhibitor of viral cell entry with a molecule blocking IL-6, a key mediator of SARSCoV-2-induced hyperinflammation. Through this dual action, this molecule may have the potential to efficiently ameliorate symptoms of COVID-19 in infected individuals. |
| تدمد: | 1098-5514 0022-538X |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0fd42612995dd16710f6b5eb64d3baa2 https://doi.org/10.1128/jvi.01622-21 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....0fd42612995dd16710f6b5eb64d3baa2 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10985514 0022538X |
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