Neuropilin-2 is an entry receptor for Chikungunya virus

Abstract Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that causes acute febrile illness and chronic arthralgia, yet no approved antivirals exist. Although MXRA8 was previously identified as a CHIKV receptor, it cannot account for viral infection in MXRA8 absence both in vitro and in vivo , suggesting additional entry mediators. Here, we identify neuropilin-2 (NRP2) as a functional entry receptor for CHIKV. Through targeted siRNA screening in neural cells, we found NRP2 to be critical for viral entry independently of MXRA8. The extracellular domain of NRP2 binds directly to the CHIKV E2 glycoprotein, with defined amino acid residues mediating this interaction. NRP2 and MXRA8 function additively and non-competitively, expanding the known cellular entry landscape for CHIKV. Monoclonal antibodies targeting NRP2 or a soluble NRP2-Fc decoy potently inhibit CHIKV infection in vitro and in vivo , moreover attenuate joint pathology in a murine model. These findings establish NRP2 as a key entry receptor for CHIKV, explaining its broad tissue tropism and presenting a promising target for therapeutic intervention.