DC/L-SIGN recognition of spike glycoprotein promotes SARS-CoV-2 trans-infection and can be inhibited by a glycomimetic antagonist

Abstract

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 (CLRS) 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.

Identification of lectin receptors for conserved SARS‐CoV‐2 glycosylation sites

“…Here we report the results from unbiased screening of a comprehensive mammalian lectin library for potent SARS‐CoV‐2 Spike binding, identifying mouse CD209c and Clec4g, as well as their human homologs hCD209 and hCLEC4G, as N‐glycan dependent Spike receptors. hCD209 has been identified as candidate receptor for SARS‐CoV‐2 by other groups, and other lectins have been also implicated in cellular interactions with Spike (preprint: Gao et al , 2020 ; Thépaut et al , 2021 ). CLEC4G has been reported to associate with SARS‐CoV (Gramberg et al , 2005 ).…”

Monocytes and Macrophages in COVID-19

“…Furthermore, C-type lectin receptors, including DC-SIGN, L-SIGN, LSECtin, ASGR1, CLEC4K (Langerin) and CLEC10A (MGL), as well as Tweety family member 2 have been identified to interact with the SARS-CoV-2 spike protein inducing proinflammatory responses, but not allowing direct infection. Notably, however, these interactions were shown to promote virus transfer to ACE + cells ( 120 , 121 ).…”

SARS-CoV-2 S glycoprotein binding to multiple host receptors enables cell entry and infection

“…CLRs are involved in the detection of carbohydrate molecular patterns found on pathogens, and consequently in immune response [ 39 , 40 ]. The expression of a wide variety of CLRs on different types of innate immune cells enables fine-tuning of immune response after carbohydrate ligand binding [ 41 ]. Under inflammatory conditions, monocytes that usually circulate in the blood, bone marrow, and spleen infiltrate mucosal or inflamed tissues where they differentiate into DCs or macrophages.…”

“…While DCs are localized at mucous and epithelial interfaces (including nasopharyngeal and pulmonary mucosae), macrophages are found in the lung alveoli. It was postulated that CLR and APCs play a role in SARS-CoV-2 cell attachment and immune system activation [ 41 ]. Approximately one-third of SARS-CoV-2 S glycoprotein N-glycans are of oligomannose type [ 7 ] making them suitable ligands for DC-SIGN, L-SIGN, and Langerin.…”

“…Earlier research has demonstrated the binding of Fc-CLR constructs based on MGL and DC-SIGN to a commercial SARS-CoV-2 RBD domain [ 47 ]. Of cautionary note that Fc-CRD constructs might have different avidity properties compared to the entire CLR ectodomain, and RBD on the other hand contains 2 N-glycosylation sites, while 66 N-glycosylation sites are found on the whole S glycoprotein, potentially leading to results that would otherwise not have been found in the case of full-structure proteins [ 41 ].…”