Siglec-1 on dendritic cells mediates SARS-CoV-2 trans-infection of target cells while on macrophages triggers proinflammatory responses

Abstract

COVID-19 pandemic is not yet under control by vaccination, and effective antivirals are critical for preparedness. Here we report that macrophages and dendritic cells, key antigen presenting myeloid cells (APCs), are largely resistant to SARS-CoV-2 infection. APCs effectively captured viruses within cellular compartments that lead to antigen degradation. Macrophages sense SARS-CoV-2 and released higher levels of cytokines, including those related to cytokine storm in severe COVID-19. The sialic acid-binding Ig-like lectin 1 (Siglec-1/CD169) present on APCs, which interacts with sialylated gangliosides on membranes of retroviruses or filoviruses, also binds SARS-CoV-2 via GM1. Blockage of Siglec-1 receptors by monoclonal antibodies reduces SARS-CoV-2 uptake and transfer to susceptible target cells. APCs expressing Siglec-1 and carrying SARS-CoV-2 are found in pulmonary tissues of non-human primates. Single cell analysis reveals the in vivo induction of cytokines in those macrophages. Targeting Siglec-1 could offer cross-protection against SARS-CoV-2 and other enveloped viruses that exploit APCs for viral dissemination, including those yet to come in future outbreaks.

The impact of DAMP-mediated inflammation in severe COVID-19 and related disorders

“…While other potential receptors have been described for SARS-CoV-2, ACE2 appears to be the primary receptor, and cells that do not express ACE2 are generally resistant to infection [12] . This is consistent with the observation that the virus primarily infects epithelial cells of the lung and gut which express ACE2, although it has also been suggested that SARS-CoV-2 can infect other cell types within the body, including cardiomyocytes, neurons, endothelial cells, and some leukocytes [13] , [14] , [15] , [16] , [17] , [18] , [19] .…”

“…For instance, sialylated secreted glycoproteins from SARS-CoV-2 can bind to and activate host Siglecs thus downregulating the antiviral response [104] . Furthermore, SARS-CoV-2 viral spike proteins contain α2,6 and α2,3 linked sialic acids that enable their interaction with Siglec-1, Siglec-3, Siglec-9, and Siglec-10, facilitating their entry into host immune cells [19] , [105] , a phenomenon which can be blocked with an anti-Siglec-1 monoclonal antibody [19] ( Figure. 1 A ).…”

“…(A) Viral capture and uptake by Siglec-1 on myeloid antigen presenting cells (APCs) leads to cytokine storm and viral propagation. Anti-Siglec-1 monoclonal antibodies (mAbs) can block uptake of SARS-CoV-2 and inhibit trans-infection of target cells expressing ACE2/TMPRSS2 [19] . (B) SARS-CoV-2 pathogen/damage-associated molecular pattern (PAMP and DAMP)-mediated pattern recognition receptor (PRR) stimulation leads to production of pro-inflammatory neutrophil extracellular traps (NETosis), that propagate the hyperinflammatory cascade in COVID-19.…”

Heterogeneous Infectivity and Pathogenesis of SARS-CoV-2 Variants Beta, Delta and Omicron in Transgenic K18-hACE2 and Wildtype Mice

“…The biologic biosafety committee of Germans Trias i Pujol Research Institute (IGTP) approved the execution of SARS-CoV-2 experiments at the BSL3 laboratory of the Centre for Bioimaging and Comparative Medicine (CSB-20-015-M8; CMCiB, Badalona, Spain). The SARS-CoV-2 variants used in this study were isolated from nasopharyngeal swabs of hospitalized patients in Spain as described elsewhere ( Perez-Zsolt et al, 2021 ; Rodon et al, 2021 ). Briefly, viruses were propagated in Vero E6 cells (CRL-1586; ATCC, Virginia, VA, United States) for two passages and recovered by supernatant collection.…”

SARS-CoV-2 B.1.351 (beta) variant shows enhanced infectivity in K18-hACE2 transgenic mice and expanded tropism to wildtype mice compared to B.1 variant

“…The biologic biosafety committee of Germans Trias i Pujol Research Institute (IGTP) approved the execution of SARS-CoV-2 experiments at the BSL3 laboratory of the Centre for Bioimaging and Comparative Medicine (CMCiB, Badalona, Spain). The SARS-CoV-2 variants used in this study were isolated from nasopharyngeal swabs of hospitalised patients in Spain as described elsewhere (Perez-Zsolt et al, 2021; Rodon et al, 2021). Briefly, viruses were propagated in VeroE6 cells (CRL-1586; ATCC, Virginia, VA, USA) for two passages and recovered by supernatant collection.…”