Clinical, Virological, and Pathological Outcomes Associated with Viral Dose in AG129 Mice Infected with Chikungunya Virus: An In Vivo Model to Study Viral Pathogenesis and Antiviral Preclinical Evaluation

Chikungunya virus (CHIKV) infection presents a wide spectrum of clinical outcomes, ranging from mild self-limiting disease to severe and fatal manifestations, which are influenced by both host and viral factors. Animal models are essential for elucidating CHIKV pathogenesis and for preclinical evaluation of antiviral strategies; however, a well-characterized model evaluating the effect of different viral doses in AG129 mice remains limited. In this study, we investigated the clinical, virological, and pathological outcomes of CHIKV infection in male AG129 mice inoculated intraperitoneally with different viral doses (10, 100, and 1000 PFU/mL) of a Brazilian strain belonging to the East/Central/South African (ECSA) lineage. Lower-dose inoculation (10 PFU/mL) resulted in a milder disease course, characterized by transient viremia, limited tissue viral dissemination, minimal histopathological alterations, partial survival, and viral clearance. In contrast, higher doses (≥100 PFU/mL) led to rapid systemic viral dissemination, severe histopathological damage in the spleen, liver, and kidneys, and uniform lethality. Viral RNA was detected in serum and multiple organs in a time-dependent manner, with limited differences among inoculum doses in most tissues. Notably, dose-related differences were observed in specific compartments and time points, particularly in hind-limb muscles at early time points and in serum at later stages.