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bioRxiv · 10.64898/2025.12.04.692277

How an arthropod-borne virus manages host switches: exploration of host-specific mutations and gene formula in bluetongue virus

Moreau, Y.·Gil, P.·Exbrayat, A.·Rakotoarivony, I.·Breard, E.·Sailleau, C.·Viarouge, C.·Zientara, S.·Savini, G.·Goffredo, M.·Mancini, G.·Loire, E.·Gutierrez, S.
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Abstract

Arthropod-borne viruses, also known as arboviruses, cause disease worldwide. These viruses alternate between vertebrates and arthropods, facing distinct selection pressures in each host type. Surprisingly, whether specific mechanisms facilitate host alternation remains unclear. Here, we use bluetongue virus (BTV) as a model to investigate two phenomena potentially facilitating host alternation: adaptive mutations and genome formula variation (GFV). First, we searched for mutations indicative of host adaptation in cattle, sheep, and midges infected during an epizooty. We found a limited number of parallel mutations. This result suggests that adaptive mutations are not a main mechanism facilitating host alternation in BTV. Second, we investigated a link of GFV with a proxy of viral fitness, the speed of virus dissemination in midges. We analyzed the genome formula (GF) in experimentally-infected Culicoides imicola midges, either with an infection disseminated into the head or not. GFs differed between dissemination levels, suggesting a link between GF and the speed of virus dissemination. Finally, we investigated the mechanisms underlying GF generation. Currently, two scenarios have been proposed: random generation followed by selection, or directed generation through molecular mechanisms. To limit the influence of selection, we analyzed the GF after a single replication cycle in cell culture. GF values converged towards specific values among replicates. Moreover, GFs differed between arthropod and vertebrate cells. Thus, GF generation is not purely stochastic and is probably influenced by host-specific mechanisms. Overall, our findings highlight GFV as a potential mechanism facilitating BTV alternation across hosts, but not classical mutation-driven evolution. Author SummaryArthropod-borne viruses are important public health problems in the world. These viruses follow a complex cycle involving alternation between arthropods and vertebrates. Surprisingly, we know little on the mechanisms that facilitate alternation between the two host types. Knowledge on such mechanisms could allow the development of antiviral tools. Here, using Bluetongue virus as a model, we investigated two potential mechanisms facilitating alternation: adaptive mutations and genome formula variation (GFV). We found limited evidence for host-specific mutations in natural populations. We observed a potential link between GFV and viral fitness. Moreover, our results suggest that molecular mechanisms generate GFV in a host-specific way from the first round of cell infection.

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Moreau, Y., Gil, P., Exbrayat, A., Rakotoarivony, I., Breard, E., Sailleau, C., Viarouge, C., Zientara, S., Savini, G., Goffredo, M., Mancini, G., Loire, E., Gutierrez, S.. 2025-12-04. How an arthropod-borne virus manages host switches: exploration of host-specific mutations and gene formula in bluetongue virus. https://doi.org/10.64898/2025.12.04.692277

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