Cyclophilin–CD147 interaction enables SARS-CoV-2 infection of human monocytes and their activation via Toll-like receptors 7 and 8
Monocytes and macrophages, as important constituents of the innate immune system, are equipped with multiple Toll-like-receptors (TLRs) to recognize invading pathogens, such as SARS-CoV-2, and mount an antiviral response. Nevertheless, their uncontrolled activation can lead to hyperinflammation seen...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2025-02-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1460089/full |
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| author | Gabor Tajti Laura Gebetsberger Gregor Pamlitschka Katharina Aigner-Radakovics Judith Leitner Peter Steinberger Hannes Stockinger Anna Ohradanova-Repic |
| author_facet | Gabor Tajti Laura Gebetsberger Gregor Pamlitschka Katharina Aigner-Radakovics Judith Leitner Peter Steinberger Hannes Stockinger Anna Ohradanova-Repic |
| author_sort | Gabor Tajti |
| collection | DOAJ |
| description | Monocytes and macrophages, as important constituents of the innate immune system, are equipped with multiple Toll-like-receptors (TLRs) to recognize invading pathogens, such as SARS-CoV-2, and mount an antiviral response. Nevertheless, their uncontrolled activation can lead to hyperinflammation seen in severe COVID-19. Surprisingly, we observed that recombinant SARS-CoV-2 Spike (S) and Nucleocapsid (N) proteins triggered only a weak proinflammatory response in human peripheral blood monocytes. By employing THP-1 and Jurkat NF-κB::eGFP reporter cell lines expressing specific TLRs, various TLR ligands and blocking antibodies, we determined that surface TLRs, including TLR2/1, TLR2/6 and TLR4 do not play a major role in SARS-CoV-2 sensing. However, monocytes are potently activated by the replication-competent SARS-CoV-2, and the response correlates with the viral uptake that is observed only in monocytes, but not in lymphocytes. We show that monocyte activation involves two distinct steps. Firstly, SARS-CoV-2 infects monocytes in a process independent of the S protein and the prime SARS-CoV-2 receptor angiotensin-converting enzyme 2. Instead, the alternative SARS-CoV-2 receptor CD147, which is highly expressed on monocytes, recognizes its well-known interaction partners cyclophilins A and B that are incorporated into SARS-CoV-2 virions. Secondly, upon viral uptake via the cyclophilin-CD147 interaction, that can be inhibited by specific CD147 blocking antibodies or competition with recombinant human cyclophilin A and B, SARS-CoV-2 RNA is recognized by TLR7/8 in endosomes, leading to upregulation of tumor necrosis factor (TNF), interleukin (IL)-1β and IL-6, comprising the core hyperinflammatory signature. Taken together, our data reveal a novel mechanism how human monocytes sense SARS-CoV-2 and suggest that targeting the cyclophilin-CD147 axis might be beneficial to alleviate overt myeloid-driven inflammation triggered by SARS-CoV-2 infection. |
| format | Article |
| id | doaj-art-41a60f12f3c042cd8a75bfa1e8b28852 |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-41a60f12f3c042cd8a75bfa1e8b288522025-02-03T06:33:53ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-02-011610.3389/fimmu.2025.14600891460089Cyclophilin–CD147 interaction enables SARS-CoV-2 infection of human monocytes and their activation via Toll-like receptors 7 and 8Gabor Tajti0Laura Gebetsberger1Gregor Pamlitschka2Katharina Aigner-Radakovics3Judith Leitner4Peter Steinberger5Hannes Stockinger6Anna Ohradanova-Repic7Medical University of Vienna, Center for Pathophysiology, Infectiology and Immunology, Institute for Hygiene and Applied Immunology, Vienna, AustriaMedical University of Vienna, Center for Pathophysiology, Infectiology and Immunology, Institute for Hygiene and Applied Immunology, Vienna, AustriaMedical University of Vienna, Center for Pathophysiology, Infectiology and Immunology, Institute for Hygiene and Applied Immunology, Vienna, AustriaMedical University of Vienna, Center for Pathophysiology, Infectiology and Immunology, Institute of Immunology, Vienna, AustriaMedical University of Vienna, Center for Pathophysiology, Infectiology and Immunology, Institute of Immunology, Vienna, AustriaMedical University of Vienna, Center for Pathophysiology, Infectiology and Immunology, Institute of Immunology, Vienna, AustriaMedical University of Vienna, Center for Pathophysiology, Infectiology and Immunology, Institute for Hygiene and Applied Immunology, Vienna, AustriaMedical University of Vienna, Center for Pathophysiology, Infectiology and Immunology, Institute for Hygiene and Applied Immunology, Vienna, AustriaMonocytes and macrophages, as important constituents of the innate immune system, are equipped with multiple Toll-like-receptors (TLRs) to recognize invading pathogens, such as SARS-CoV-2, and mount an antiviral response. Nevertheless, their uncontrolled activation can lead to hyperinflammation seen in severe COVID-19. Surprisingly, we observed that recombinant SARS-CoV-2 Spike (S) and Nucleocapsid (N) proteins triggered only a weak proinflammatory response in human peripheral blood monocytes. By employing THP-1 and Jurkat NF-κB::eGFP reporter cell lines expressing specific TLRs, various TLR ligands and blocking antibodies, we determined that surface TLRs, including TLR2/1, TLR2/6 and TLR4 do not play a major role in SARS-CoV-2 sensing. However, monocytes are potently activated by the replication-competent SARS-CoV-2, and the response correlates with the viral uptake that is observed only in monocytes, but not in lymphocytes. We show that monocyte activation involves two distinct steps. Firstly, SARS-CoV-2 infects monocytes in a process independent of the S protein and the prime SARS-CoV-2 receptor angiotensin-converting enzyme 2. Instead, the alternative SARS-CoV-2 receptor CD147, which is highly expressed on monocytes, recognizes its well-known interaction partners cyclophilins A and B that are incorporated into SARS-CoV-2 virions. Secondly, upon viral uptake via the cyclophilin-CD147 interaction, that can be inhibited by specific CD147 blocking antibodies or competition with recombinant human cyclophilin A and B, SARS-CoV-2 RNA is recognized by TLR7/8 in endosomes, leading to upregulation of tumor necrosis factor (TNF), interleukin (IL)-1β and IL-6, comprising the core hyperinflammatory signature. Taken together, our data reveal a novel mechanism how human monocytes sense SARS-CoV-2 and suggest that targeting the cyclophilin-CD147 axis might be beneficial to alleviate overt myeloid-driven inflammation triggered by SARS-CoV-2 infection.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1460089/fullSARS-CoV-2CD147cyclophilinToll-like receptormonocyteantiviral innate immunity |
| spellingShingle | Gabor Tajti Laura Gebetsberger Gregor Pamlitschka Katharina Aigner-Radakovics Judith Leitner Peter Steinberger Hannes Stockinger Anna Ohradanova-Repic Cyclophilin–CD147 interaction enables SARS-CoV-2 infection of human monocytes and their activation via Toll-like receptors 7 and 8 Frontiers in Immunology SARS-CoV-2 CD147 cyclophilin Toll-like receptor monocyte antiviral innate immunity |
| title | Cyclophilin–CD147 interaction enables SARS-CoV-2 infection of human monocytes and their activation via Toll-like receptors 7 and 8 |
| title_full | Cyclophilin–CD147 interaction enables SARS-CoV-2 infection of human monocytes and their activation via Toll-like receptors 7 and 8 |
| title_fullStr | Cyclophilin–CD147 interaction enables SARS-CoV-2 infection of human monocytes and their activation via Toll-like receptors 7 and 8 |
| title_full_unstemmed | Cyclophilin–CD147 interaction enables SARS-CoV-2 infection of human monocytes and their activation via Toll-like receptors 7 and 8 |
| title_short | Cyclophilin–CD147 interaction enables SARS-CoV-2 infection of human monocytes and their activation via Toll-like receptors 7 and 8 |
| title_sort | cyclophilin cd147 interaction enables sars cov 2 infection of human monocytes and their activation via toll like receptors 7 and 8 |
| topic | SARS-CoV-2 CD147 cyclophilin Toll-like receptor monocyte antiviral innate immunity |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1460089/full |
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