Flavivirus assembly is driven by the envelope glycoproteins pre-membrane (prM) and envelope (E) in the neutral pH environment of the endoplasmic reticulum. Newly budded, spiky particles are exported through the Golgi apparatus, where mildly acidic pH induces a major surface rearrangement. The glycoproteins reorganize into (prM/E)\₂ complexes at the surface of smooth particles, with prM trapped at the E dimer interface, thereby exposing a furin cleavage site (FCS) for proteolytic maturation into infectious virions. Here, we show that in the absence of furin, immature tick-borne flavivirus particles-tick-borne encephalitis virus, Langat virus, and Louping ill virus-remain fully infectious and pathogenic in female BALB/c mice, in contrast to mosquito-borne flaviviruses such as Usutu, West Nile, and Zika viruses. We further show that the FCS in tick-borne viruses remains exposed at neutral pH, allowing furin at the surface of target cells to activate viral fusogenicity, while mosquito-borne counterparts require acidic re-exposure. Mutations increasing the dynamic behavior of the E dimer mimic the mosquito-borne phenotype, with retracted FCS at neutral pH and loss of infectivity. Our multidisciplinary approach-combining virological assays, targeted mutagenesis, structural modeling, and molecular dynamics simulations-highlights the role of E dimer dynamics in regulating flavivirus maturation and infectivity.

• Publikační typ
• časopisecké články MeSH

Ticks and tick-borne diseases are a growing burden worldwide and vaccines are effective control interventions. Vaccine formulations with tick antigens such as BM86/BM95 (BM) and Subolesin (SUB) have shown reduction in tick fitness and infestation in immunized hosts. However, antigen combination is a challenging approach to improve vaccine efficacy (E) against multiple tick species. Herein, in silico and in music algorithms were integrated to model BM-SUB protein-protein interactions to apply a quantum vaccinology approach for combining protective epitopes or immunological quantum in the chimeric antigen Q38-95. Cattle immunized with Q38-95 and infested with African blue tick Rhipicephalus decoloratus showed an 82% E similar to BM86 and higher than SUB. The immune mechanisms activated in cattle in response to vaccination with Q38-95 were mediated by anti-BM/SUB antibodies that interfered with BM-SUB interactions and through activation of other innate and adaptive immune pathways. The results support modelling protein-protein interactions affecting E to identify and combine candidate protective epitopes in chimeric antigens.

• MeSH
• antigeny * imunologie   chemie   MeSH
• epitopy * imunologie   chemie   MeSH
• infestace klíšťaty * prevence a kontrola   imunologie   veterinární   MeSH
• Rhipicephalus imunologie   MeSH
• skot MeSH
• vakcíny * imunologie   MeSH
• zvířata MeSH
• Check Tag
• skot MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antigeny * MeSH
• epitopy * MeSH
• vakcíny * MeSH