Cyclophilin-CD147 interaction facilitates SARS-CoV-2 entry and Toll-Like Receptor 7/8-mediated activation of human monocytes 9224

Description G. Tajti1,2, L. Gebetsberger1, G. Pamlitschka1, R. Klasinc1, K. Aigner-Radakovics3, J. Leitner3, P. Steinberger3, H. Stockinger1, A. Ohradanova-Repic1 Medical University of Vienna, Center Pathophysiol., Infectiol. & Immunol., 1Inst. Hygiene & Applied Immunol., and 3Inst. Immunol.; Center Physiol. & Pharmacol., 2Inst. Physiol. Monocytes, as key players of innate immunity, are essential for coordinating antiviral responses. However, the mechanisms by which they directly detect SARS-CoV-2 remain unclear. Given the critical role of Toll-like receptors (TLRs) in pathogen recognition, we investigated whether and how monocytes are activated by SARS-CoV-2 through TLR. Because monocytes lack expression of the canonical SARS-CoV-2 receptor ACE2, we examined also which alternative viral entry pathway is utilized by SARS-CoV-2 for infection. Our study revealed three major findings: (1) Circulating monocytes from healthy donors are activated by SARS-CoV-2 primarily through pathways that minimally involve surface-expressed TLRs. (2) SARS-CoV-2 can enter and infect monocytes via a non-classical pathway independent of the Spike protein-ACE2 interaction. This process involves host-derived cyclophilins interacting with the immunoglobulin family member CD147, which is highly expressed on the monocyte surface. (3) Endosomal single-stranded RNA-sensing TLRs, particularly TLR7 and TLR8, play a central role in driving the proinflammatory activation of monocytes in response to SARS-CoV-2. Funding Sources This work is supported by the Austrian Science Fund (FWF) grant P 34253-B.