Usutu virus uses langerin as a receptor to productively infect Langerhans cells more efficiently than West Nile virus

Usutu virus (USUV) and West Nile virus (WNV) are emerging flaviviruses transmitted by mosquitoes. Although they differ in their endemicity, with WNV present throughout much of the world and USUV currently limited to Africa and Europe, both constitute a global public health threat. Since they are directly inoculated in the epidermis and the dermis during mosquito bites, the skin constitutes the initial site of viral replication and immune response. The skin is equipped with a unique network of dendritic cells, which represent an essential outpost of immune defenses. These skin-resident DCs comprise Langerhans cells (LCs) in the epidermis and dermal DCs in the dermis, which capture pathogens through the C-type lectin receptors (CLR) langerin and DC-SIGN, respectively. Despite the key role of these cells in the body’s antiviral defenses, their implication in the immune control and replication of WNV and USUV is not known.Using human skin explants, we show that while both viruses can replicate in keratinocytes, they can also infect resident DCs with distinct tropism, since WNV preferentially infects DCs in the dermis, whereas USUV has a greater propensity to infect LCs. Using both purified human epidermal LCs (eLCs) and monocyte derived LCs (MoLCs), we confirm that LCs sustain a faster and more efficient replication of USUV compared with WNV and that this correlates with a more intense innate immune response to USUV compared with WNV.Next, we show that ectopic expression of langerin in non-permissive cells rendered them permissive to USUV, but not to WNV. Conversely, blocking or silencing langerin in MoLCs or eLCs made them resistant to USUV infection, thus demonstrating that this specific CLR allows USUV to enter and productively infect LCs.Altogether, our results demonstrate that LCs constitute privileged target cells for USUV in human skin, because langerin favors its entry and replication. Intriguingly, this suggests that USUV efficiently escapes the antiviral functions of langerin, which normally safeguards LCs from most viral infections.