The previously known route of infection by SARS-CoV-2 is via a specific receptor on cells (ACE2), to which the virus's concisely formed spike protein binds. As a special unit of the immune system, monocytes do not have ACE2 receptors. How they are still able to recognise and fight SARS-COV-2 is something that scientists have not yet been able to explain. The research team led by Anna Ohradanova-Repic and Hannes Stockinger from MedUni Vienna's Center for Pathophysiology, Infectiology and Immunology has now described the underlying mechanism for the first time.
Alternative entry point
As the study shows, SARS-CoV-2 hijacks certain omnipresent proteins (cyclophilin A and B) in the body to bind to a receptor on the surface of monocytes (CD147). "Coronaviruses probably use this alternative route of infection for other cells that lack ACE2," explains study leader Anna Ohradanova-Repic. Since the cell components used in this infection pathway are found practically everywhere in the body, this alternative entry point expands the range of the virus – a possible reason why COVID-19 can affect such a wide range of areas in the organism. "In addition, the entry mechanism of SARS-CoV-2 that we have discovered can also increase the viral load in infected cells and worsen the course of the disease," adds co-study leader Hannes Stockinger.
Monocytes strike back
Despite being infected with SARS-CoV-2, the central finding of the research is that monocytes cannot be outmanoeuvred by SARS-CoV-2 and launch a counterattack. In doing so, they use the newly discovered mechanism (cyclophilin-CD147 axis) to kill and recognise the virus. This triggers an inflammatory response that activates the immune system and strengthens the defence with additional immune cells. An over-activation of this mechanism could explain the excessive inflammatory response observed in severe COVID-19 cases, which can lead to tissue damage and organ failure. "Thus, our results provide valuable insights into how the immune response could be modulated to treat patients with severe COVID-19," says Anna Ohradanova-Repic, who is planning further studies to deepen the findings.
Publication: Frontiers in Immunology
Cyclophilin-CD147 interaction enables SARS-CoV-2 infection of human monocytes and their activation via Toll-like receptors 7 and 8.
Gabor Tajti, Laura Gebetsberger, Gregor Pamlitschka, Katharina Aigner-Radakovics, Judith Leitner, Peter Steinberger, Hannes Stockinger and Anna Ohradanova-Repic
DOI: 10.3389/fimmu.2025.1460089
https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1460089