ArticleFrontiers in immunology2025
Cyclophilin-CD147 interaction enables SARS-CoV-2 infection of human monocytes and their activation via Toll-like receptors 7 and 8.
Article in Frontiers in immunology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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Who cites it
3 citing papers in PubMed.
- In silico design of a novel multi-epitope mRNA vaccine candidate for BtHKU5-CoV-2 using immunoinformatics.PLoS neglected tropical diseases · 2026Article
- Cyclophilins as key players in protozoan parasite infections.Parasites & vectors · 2025Review
- Persistent Monocytic Bioenergetic Impairment and Mitochondrial DNA Damage in PASC Patients with Cardiovascular Complications.International journal of molecular sciences · 2025Article
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8 authors.
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Abstract
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.
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