Antigen-presenting cells (APCs) may be resistant to SARS-CoV-2 infection but still contribute to viral pathogenesis. Lectins such as sialic acid-binding Ig-like lectin 1 (Siglec-1/CD169) mediate the attachment of viruses to APCs. Here, we show that APCs effectively capture SARS-CoV-2 within compartments via recognition of Siglec-1. This receptor interacts with sialylated gangliosides on membranes of SARS-CoV-2 variants, as previously shown for retroviruses or filoviruses [1]. Blockage of Siglec-1 on monocyte-derived dendritic cells (MDDCs) decreased SARS-CoV-2 viral transfer or trans-infection to bystander target cells. However, monocyte-derived macrophages (MDMs) capturing SARS-CoV-2 via Siglec-1 did not transmit infectious particles. The presence of pulmonary APCs co-expressing Siglec-1 and SARS-CoV-2 corroborated these findings in vivo. We used the methodology described in the Supplementary Methods to dissect the contribution of Siglec-1 to SARS-CoV-2 pathogenesis. Siglec-1 expression is induced on APCs upon IFN-α or LPS exposure and increased in myeloid cells of COVID-19 patients [2]. Here, we tested whether this lectin could bind SARS-CoV-2 via recognition of sialylated gangliosides on viral membranes. APCs captured incoming SARS-CoV-2 in cellular compartments, eventually leading to viral degradation (Supplementary Fig. 1, 2). Raji B cell lines transfected with different lectins (Supplementary Fig. 3A) were pulsed with SARS-CoV-2, washed and assessed by ELISA to measure cell-associated viral nucleocapsid content (Fig. 1 A). While Raji cells trasnfected with wild-type Siglec-1 captured SARS-CoV-2, cells transfected with DC-SIGN, Siglec-5, Siglec-7 or devoid of these lectins did not (Fig. 1 A). Viral uptake via Siglec-1 relied on the recognition of sialylated ligands, as observed with Raji cells transfected with the Siglec-1 mutant R116A, which lacks sialic acid recognition capacity and did not trap SARS-CoV-2 (Fig. 1 A). Raji cells pretreated with the α-Siglec-1 monoclonal antibody (mAb) 7-239 reduced SARS-CoV-2 uptake (Supplementary Fig. 3B). SARS-CoV-2 variants were equally trapped via Siglec-1 but not by the mutated Siglec-1 R116A, indicating that sialic acid recognition is critical (Fig. 1 B). Superresolution microscopy of SARS-CoV-2 confirmed that GM1, one of the sialyllactose-containing gangliosides interacting with Siglec-1 [1], was detectable on 74% of virus particles (Fig. 1 C). MDMs and MDDCs treated with IFN-α to induce Siglec-1 expression displayed higher SARS-CoV-2 uptake than nonactivated cells (Fig. 1 D), and uptake was blocked by the α-Siglec-1 mAb 7-239 (Fig. 1 E). These complementary approaches identified Siglec-1 as a central molecule mediating SARS-CoV-2 uptake via sialic acid recognition. Once Siglec-1 binds to HIV-1 or Ebola viruses, receptors polarize and engulf particles within viral-containing compartments (VCCs) that are continuous with the plasma membrane and connected to the extracellular space [1]. To elucidate whether Siglec-1 also recruits SARS-CoV-2 to VCCs, we used confocal and electron microscopy and found Siglec-1-positive VCCs containing viral particles on activated MDDCs (Fig. 1 F, G and Movie 1). Siglec-1 has a dual role in enhancing infectivity, either facilitating fusion on APCs, as is the case for the Ebola virus, or mediating transmission to other target cells in trans, as is the case for retroviruses [1]. Since SARS-CoV-2 fusion on APCs is limited (Supplementary Fig. 1B), we explored the relevance of viral trans-infection. Raji cells were exposed to SARS-CoV-2, washed and cocultured with targets expressing or not expressing ACE2 (Fig. 1 H). Raji Siglec-1 …