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Adaptation to mosquito vectors suited for transmission in urban settings is a major driver in the emergence of arboviruses. To better anticipate future emergence events, it is crucial to assess their potential to adapt to new vector hosts. In this work, we used two different experimental evolution approaches to study the adaptation process of an emerging alphavirus, Mayaro virus (MAYV), to Aedes aegypti, an urban mosquito vector of many arboviruses. We identified E2-T179N as a key mutation increasing MAYV replication in insect cells and enhancing transmission by live Aedes aegypti. In contrast, this mutation decreased viral replication and binding in human fibroblasts, a primary cellular target of MAYV in humans. We also showed that MAYV E2-T179N was attenuated in vivo in a mouse model. We then used structural and experimental analyses to show that MAYV E2-T179N bound less efficiently to human cells, though the decrease in replication or binding was not mediated through interaction with one of the host receptors, Mxra8. When this mutation was introduced in the closely related chikungunya virus, which has caused major outbreaks globally in the past two decades, we observed increased replication in both human and insect cells, suggesting E2 position 179 is an important determinant of alphavirus host-adaptation, although in a virus-specific manner. Collectively, these results indicate that adaptation at the T179 residue in MAYV E2 may result in increased vector competence – but coming at the cost of optimal replication in humans – and may represent a first step towards a future emergence event.

Mosquito-borne …