Anti-Siglec-1 antibodies block Ebola viral uptake and decrease cytoplasmic viral entry

When Dendritic Cells Go Viral: The Role of Siglec-1 in Host Defense and Dissemination of Enveloped Viruses

“…C-type lectin receptors (CLRs) such as the dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) and the liver/lymph node sinusoidal endothelial C-type lectin (LSECtin) mediate viral attachment through binding to viral glycoproteins [106,107], while receptors of the TIM/TAM families (comprising the T cell immunoglobulin and mucin domain receptor along with Tyro-Axl-Mer receptors) recognize phosphatidylserine lipids present on the viral envelope [108] ( Figure 2B). EBOV incorporates sialylated gangliosides on their membrane [27], and we have recently shown that these viruses are effectively recognized by the Siglec-1 receptor [22] ( Figure 2B).…”

“…DCs are highly susceptible to EBOV infection [11,103], and this is a complex process that involves several host factors whose function is still being identified [104]. Indeed, Siglec-1 expressed on activated DCs has recently emerged as a new host factor implicated in EBOV attachment, a mechanism that facilitates subsequent cytoplasmic viral entry [22] ( Figure 2B).…”

“…Siglec-1 recognition of sialylated gangliosides on EBOV modulates the binding, uptake, and trafficking of filoviral particles into a sac-like virus-containing compartment (VCC) continuous with the plasma membrane ( Figure 2B). Viruses stored in this compartment can be redirected into the classical endosomal pathway and facilitate viral entry into the cytoplasm [22]. Indeed, EBOV macropinocytosis allows trafficking into late endosomes, where cleavage of viral glycoproteins by cathepsin B (CTSB) facilitates the interaction with the endosomal receptor Niemann-Pick C1 [109][110][111] (NCP1) that triggers cytoplasmic viral entry [112][113][114] (Figure 2B).…”

“…The discovery of the role of the receptor Siglec-1/CD169, a sialic acid-binding Ig-like lectin-1 expressed by DCs, has greatly contributed to our understanding of how viruses subvert DC activity. The Siglec-1 receptor acts as an immuno-surveillance molecule [19] but can also be effectively hijacked by distinct enveloped viruses, which either infect DCs directly or are effectively transferred to bystander target cells that become productively infected [20][21][22]. Hence, Siglec-1 function on DCs clearly illustrates how these APCs can trigger antiviral immunity but also enhance viral spread via this receptor.…”

“…Siglec-1 is a type I transmembrane lectin with an amino-terminal V-set domain that interacts with sialylated ligands, preferentially N-acetylneuraminic acid (Neu5Ac) in an α2-3 linkage [19,23]. Several enveloped viruses including human immunodeficiency virus (HIV)-1 [24][25][26] and Ebola virus (EBOV) [22,[27][28][29] incorporate such sialylated ligands within their membranes as an integral part of the gangliosides that are dragged from the plasma membrane when viruses bud from infected cells. Although Siglec-1 affinity for sialylated ligands is in the micromolar range, high-avidity binding can be achieved upon clustering of thousands of gangliosides in the viral membrane with their receptors on the cellular membrane [19,30].…”