Orthobunyavirus entry: receptors, endocytosis, and fusion cues

Orthobunyaviruses (OBVs) are medically and veterinary important arboviruses with simple genomes yet complex entry mechanisms enabling infection of diverse mammalian hosts. Understanding of the molecular and cellular processes mediating OBV attachment, internalization, endosomal trafficking, and membrane fusion has advanced recently. Here, we review how OBVs engage host receptors, notably the low-density lipoprotein receptor-related protein 1 (Lrp1), utilize clathrin-mediated endocytosis, and respond to endosomal acidification and potassium ion accumulation to trigger fusion via their class II Gc glycoprotein. Live-cell imaging has elucidated single-particle entry dynamics, revealing the interplay of viral and host factors in timing and efficiency of genome release. These findings refine the model of OBV entry, highlighting coordinated physicochemical cues and receptor usage that influence tropism and pathogenesis. Improved mechanistic insights offer potential avenues for broad-spectrum antiviral development and enhance understanding of OBV epidemiology, exemplified by Oropouche virus emergence in South America. • Lrp1 identified as the first essential entry receptor for an orthobunyavirus. • Gn/Gc structures reveal a conserved fusion core with a variable head domain. • Fusion requires acidic pH, K⁺ influx, and endosomal membrane remodeling. • Single-particle imaging captures orthobunyavirus entry with high resolution. • Entry pathways differ among species, shaping tropism and host range.