MRI of Syrian hamsters reveals SARS-CoV-2 variant-specific neuroinflammation

SARS-CoV-2 infection causes neurological manifestations in 30%–40% of patients, with reinfection exacerbating sequelae risks. Elucidating neuroinvasion mechanisms requires optimized animal models overcoming limitations of existing systems. This study establishes the Syrian hamster as a neuroanatomically optimized model to investigate SARS-CoV-2 variant-specific neuropathogenesis. Syrian hamsters subjected to primary infection and reinfection with WH-09 and Omicron subvariants (XBB.1, BA.1, or BF.7) were investigated using multimodal MRI and histopathology. We demonstrate that SARS-CoV-2 variants exhibit strikingly differential neuroinvasive capacities following primary infection and reinfection. Notably, immune-evasive variants like XBB.1 and WH-09 induced significant, unresolved damage in olfactory-limbic regions, correlating with clinical symptoms such as hyposmia. BF.7 and BA.1 exhibited minimal neurostructural alterations in both primary and reinfection models. These variant-specific neuropathological profiles, precisely mapped via MRI-histopathology correlation, underscore the model’s utility in delineating the neurological threats posed by evolving variants. IMPORTANCE This study demonstrates that Syrian hamsters offer advantages for modeling SARS-CoV-2 neuropathogenesis. WH-09 and XBB.1’s persistent olfactory and hippocampus damage, which was quantified through integrated MRI and histopathology, underscores the neurological threat posed by immune-evasive variants. Conversely, Omicron’s attenuated phenotype provides a blueprint for virulence-modifying interventions. This work establishes multimodal imaging in hamsters as an effective strategy for evaluating emerging viral variants.