Decoding tick receptor mechanisms in Kyasanur forest disease virus transmission: structural insights into vector competence

Kyasanur forest disease virus (KFDV), a tick-borne flavivirus of major zoonotic concern, is responsible for recurrent outbreaks in Southern India. Although various tick species have been implicated in KFDV transmission, the molecular determinants of viral entry and vector competence remain undefined. To investigate this, we employed in silico structural approaches integrating cross-species receptor mining, protein-protein docking, and molecular dynamics simulations. This analysis revealed conserved homologues of mammalian flavivirus and arthropod receptors across Ixodid ticks with Dermacentor and Rhipicephalus spp. having the highest receptor repertoire. Docking analyses with the KFDV envelope protein demonstrated strong interactions with heat shock protein 70 (HSP70) and C-type lectins (CTLs) from Dermacentor silvarum followed by Ornithodorus turicata and Rhipicephalus microplus. Furthermore, envelope dimerization enhanced binding with selected receptors, and simulations confirmed a stable, high-affinity envelope-D. silvarum CTL complex (ΔG = - 45.24 ± 1.28 kcal/mol), stabilized by extensive hydrogen bond networks centred on domain III residues. The observed variation in EDIII-mediated receptor binding suggests that differential structural compatibility may influence host receptor recognition and early stages of virus-vector interaction across tick species. Together, these findings provide preliminary structural insights into KFDV-tick receptor interactions and lay the molecular groundwork for understanding species-specific determinants of vector competence.