Evaluation of Neuroinflammatory and Cognitive Alterations Induced by Different SARS-CoV-2 Variants in a Murine Model

COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a systemic infection that may cause persistent neurological sequelae. However, its impact on the central nervous system (CNS) may differ according to viral variant and infection stage. This study evaluated the effects of Delta and Omicron variants on disease severity, cognitive function, and hippocampal neuroinflammatory responses during acute and late infection in K18-hACE2 transgenic mice. Animals were intranasally infected with Delta or Omicron variants and were evaluated at 7 and 30 days post-infection (dpi). Survival was monitored, and cognitive function was assessed using the step-down passive avoidance test.Hippocampal expression of antiviral, inflammatory, microglial, complement, and synaptic plasticity genes was analyzed by RT-qPCR. Delta infection caused greater disease severity, with survival declining to approximately 19.4% at 14 dpi, whereas Omicron induced a milder phenotype, with approximately 73.3% survival. Omicron did not cause detectable cognitive impairment, whereas Delta-infected animals showed a trend toward impaired aversive memory at 30 dpi. Hippocampal responses were more pronounced after Delta infection, with increased interferon alpha (IFN-α), interferon beta (IFN-β), and toll-like receptor 4 (TLR4) expression during the acute phase. At a later stage, tumor necrosis factor (TNF) expression increased, while TLR4 and Clec7a approached statistical significance. In contrast, Omicron did not induce detectable changes in neuroinflammatory, antiviral, complement, or synaptic plasticity markers. These findings indicate distinct neuroimmune profiles between variants, with Delta associated with greater disease severity, stronger hippocampal inflammatory and antiviral responses, and potential late cognitive impairment, whereas Omicron had limited impact on the CNS. 

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