Río Negro virus (Venezuelan equine encephalitis virus complex) shows pathogenic potential in a permissive murine model.

Río Negro virus (RNV), an enzootic member of the Venezuelan equine encephalitis virus (VEEV) complex, has historically been regarded as avirulent based on studies in adult immunocompetent animals. However, its pathogenic potential under biologically relevant conditions has not been systematically examined. Here, we investigated RNV infection in infant C57BL/6 mice as a permissive developmental model. Infection resulted in a transient viremic phase followed by systemic dissemination, disruption of splenic immune architecture, and pronounced neuroinflammatory and neurodegenerative alterations in the central nervous system. Viral replication in brain tissue coincided with astrocyte activation and elevated pro-inflammatory cytokine levels, indicating the establishment of immunopathological processes. These findings demonstrate that RNV retains the capacity to induce systemic and neuroinvasive disease under conditions of developmental immune immaturity. Our study provides the first comprehensive in vivo characterization of RNV pathogenesis and supports the need to consider this enzootic alphavirus within the broader context of VEEV-complex viruses potentially associated with underrecognized febrile disease in endemic regions, particularly in light of the recent report of a clinically apparent and molecularly confirmed human infection.