Molecular Mechanisms of Getah Virus Pathogenesis

Getah virus (GETV), a mosquito-borne alphavirus within the Togaviridae family, produces distinct pathological outcomes in different hosts, highlighting that viral and host molecular interactions determine disease phenotypes. For instance, horses typically develop acute febrile disease accompanied by limb edema and cutaneous rash, whereas pigs may experience reproductive failure, fetal infection, and severe neonatal disease. These host-dependent outcomes indicate that GETV pathogenesis involves the combined effects of viral entry, intracellular replication, host antiviral responses, tissue permissiveness, and viral dissemination. The E1/E2 envelope glycoproteins contribute to cellular attachment, membrane fusion, and viral entry, while the non-structural proteins nsP1–nsP4 coordinate viral RNA replication and interact with the host’s cellular pathways. Among these proteins, nsP2 contributes to suppression of antiviral responses via TBK1–IRF3 and JAK–STAT signaling, whereas nsP3 participates in replication complex formation and interactions with host factors by disruption of G3BP1-associated stress granules. Genetic variation among GETV lineages is also associated with differences in epidemiology and pathogenic strains, although the causal contribution of individual mutations remains incompletely defined. Functional studies of envelope variation, including the E2-N262 glycosylation site, further indicate that viral surface properties can influence replication and virulence. Despite increasing molecular and epidemiological evidence, important gaps remain in understanding the relative contribution of different entry factors, cellular permissiveness, host-dependent pathogenicity, and the functional consequences of naturally occurring viral variation. This review integrates the current evidence on GETV viral proteins, replication, cellular entry, host antiviral responses, tissue tropism, host-specific pathology, and viral genetic diversity to establish the current molecular framework of GETV pathogenesis and highlight the priorities for future experimental validation and disease control.