The efficient spread of SARS-CoV-2 resulted in a unique pandemic in modern history. Despite early identification of ACE2 as the receptor for viral spike protein, much remains to be understood about the molecular events behind viral dissemination. We evaluated the contribution of C-type lectin receptors (CLR S ) of antigen-presenting cells, widely present in respiratory mucosa and lung tissue. DC-SIGN, L-SIGN, Langerin and MGL bind to diverse glycans of the spike using multiple interaction areas. Using pseudovirus and cells derived from monocytes or T-lymphocytes, we demonstrate that while virus capture by the CLRs examined does not allow direct cell infection, DC/L-SIGN, among these receptors, promote virus transfer to permissive ACE2 + Vero E6 cells. A glycomimetic compound designed against DC-SIGN, enable inhibition of this process. These data have been then confirmed using authentic SARS-CoV-2 virus and human respiratory cell lines. Thus, we described a mechanism potentiating viral spreading of infection. Author summary For their infectious effectiveness, viruses often use host attachment factors to improve their adhesion to the cell surface. This will mainly increase viruses concentration at cell surfaces, potentiating access and final engagement with their real entry receptors. This mechanism enhances viral infection of target cells or even allow viruses to be captured by non-permissive cells for secondary presentation to permissive cells by a process called trans-infection. While, the entry mechanism of SARS-CoV-2 using the ACE2 entry receptor, is well defined, little is known about additional factors explaining the high transmission rate of this virus. The level of glycosylations on the SARS-CoV-2 Spike protein prompted us to assess whether CLRs of immune cells, regularly diverted by pathogens, could play a role in the spread of SARS-CoV-2. Here, we show that these receptors are able to recognize Spike envelope protein of SARS-CoV-2 and two receptors among the four tested, DC-SIGN and L-SIGN, are able to promote virus trans-infection. This work identifies a new family of alternative SARS-CoV-2 cell receptors involved in uncharacterized dissemination mechanism. Moreover, considering the role of CLRs in immunomodulation, their early involvement opens avenues for understanding the imbalanced innate immune response observed in COVID-19 pathogenesis.
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