Pathogenicity of Rift Valley fever virus: Organ-specific clinical outcomes and hidden drivers of virulence - a narrative review

Rift Valley fever virus (RVFV) is a mosquito-borne phlebovirus posing major threats to human and animal health. Despite decades of research, the determinants governing diverse clinical manifestations remain incompletely understood. This narrative review examines four central facets: i) exposure route impacts on disease outcome; ii) field strain diversity and organ-specific virulence; iii) genome reassortment driving viral evolution; and iv) organ-specific pathology including the overlooked placental/retinal infections. Differences among infection routes, viral strains, and host species complicate extrapolation from experimental models to outbreaks. Collectively, evidence indicates that RVFV pathogenesis results from interplay between infection route, viral determinants, and host factors including age and immune responses, which shape viral dissemination, tissue tropism, and organ-specific disease outcomes. Despite progress, major uncertainties remain regarding mechanisms controlling tissue tropism and field strain diversity roles in severe manifestations. Integrating field isolates, organotypic cultures, and physiologically relevant models will be essential to refine understanding and improve prevention.