SARS-CoV-2 exacerbates proinflammatory responses in myeloid cells through C-type lectin receptors and Tweety family member 2

Abstract

Despite mounting evidence for SARS-CoV-2 engagement with immune cells, most express little, if any, of the canonical receptor of SARS-CoV-2, ACE2. Here, using a myeloid-cell receptor-focused ectopic expression screen, we identified several C-type lectins (DC-SIGN, L-SIGN, LSECtin, ASGR1, and CLEC10A) and Tweety family member 2 (TTYH2) as glycan-dependent binding partners of the SARS-CoV-2 spike. Except for TTYH2, these molecules primarily interacted with spike via regions outside of the receptor-binding domain. Single-cell RNA-sequencing analysis of pulmonary cells from COVID-19 patients indicated predominant expression of these molecules on myeloid cells. Although these receptors do not support active replication of SARS-CoV-2, their engagement with virus induced robust proinflammatory responses in myeloid cells that correlated with COVID-19 severity. We also generated a bispecific anti-spike nanobody that not only blocked ACE2-mediated infection but also the myeloid receptors-mediated proinflammatory responses. Our findings suggest SARS-CoV-2-myeloid receptor interactions promote immune hyper-activation, which represents potential targets for COVID-19 therapy.

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

“…Of note, in multiple attempts to produce full‐length Spike harbouring the N343Q point mutation we observed that this is a crucial site for Spike stability and secretion (Appendix Fig S4 ). This puts in question previous conclusions drawn on Spike N343Q (Li et al , 2020 ; Lu et al , 2021 ); further studies are required to fully understand the role of specific Spike glycan sites for stability and function.…”

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 ).…”

Interfering with SARS-CoV-2: are interferons friends or foes in COVID-19?

“…RIG-I and MDA5 recognize SARS-CoV-2 RNA as well as intermediates of replication of the virus inside infected cells [ 40 , 41 , 42 ], while other PRRs are involved in virus recognition by bystander and/or non-infected cells. Several C-type lectins (such as DC-SIGN) and Tweety family member 2 (TTYH2) bind SARS-CoV-2 spike protein, and induce pro-inflammatory responses in myeloid cells [ 43 ]. In keeping with recognition of SARS-CoV-2 by non-infected cells, TLR2 binds the SARS-CoV-2 envelope to induce inflammation, in the absence of internalization of the virus [ 44 ].…”