The 3‘Untranslated region is a critical determinant of Getah virus replication, pathogenesis, and vector competence

Getah virus (GETV), a mosquito-borne arbovirus of the Alphavirus genus, poses an emerging threat to livestock economies and public health, underscored by its expanding host range and association with recent outbreaks of heightened virulence. While the functional significance of the 3' untranslated region (3'UTR) in alphavirus biology is recognized, its specific role in GETV remained undefined. Herein, we elucidate the virological functions of the GETV 3'UTR through a reverse genetics approach, generating a panel of viruses with targeted deletions. We demonstrate that the GETV 3'UTR is remarkably plastic, tolerating a consecutive deletion of up to 310 nucleotides while remaining viable. Deletion of conserved repeat sequence elements (RSEs) induced a cell-type-specific replication deficiency in vitro and significantly attenuated virulence in a murine model. A comprehensive deletion mutant (rGETV-KO310) exhibited further impaired replication kinetics in vitro and was profoundly attenuated in vivo, eliciting only transient morbidity with no mortality in both neonatal and weaned mice. Furthermore, this mutant displayed a significant defect in early colonization within mosquito vectors, indicating a role in vector competence. Comparative transcriptomic profiling of knee joints revealed that attenuation correlates with the altered modulation of critical host immune responses, notably the interferon and MAPK signaling pathways. Collectively, these findings establish the GETV 3'UTR as a pivotal regulator of viral fitness, pathogenesis, and transmission. This work provides a foundational rationale for the strategic development of live-attenuated vaccine candidates based on targeted 3'UTR attenuation.