Investigating biomarkers and therapeutic approaches in mouse models of SARS-CoV2 induced Long COVID with neuroinflammation and cognitive deficits.

Survivors of COVID-19 frequently experience lingering neurological symptoms including cognitive impairment. However, the absence of suitable animal models presents a significant challenge in comprehensively understanding the post-acute sequelae of SARS-CoV-2 (PASC) or Long COVID. Utilizing a mild SARS-CoV2 infection mouse model, we explored neuroinflammation caused by respiratory SARS-CoV2 infection in mouse with AAV-hACE2 delivery in lower respiratory system only and found white matter selective microglial reactivity. After subjecting mice to mild SARS-CoV-2 infection for 7 weeks, we observed persistently impaired hippocampal neurogenesis, decreased oligodendrocytes, and myelin loss along with increased CCL11 in cerebrospinal fluid (CSF). Notably, individuals experiencing lasting cognitive symptoms post-COVID exhibited elevated CCL11 levels, suggesting its potential as a biomarker for Long COVID. Concurrently, we developed a model of moderate mortality SARS-CoV-2 infection in K18-hACE2 transgenic mice by modifying the infection route, allowing us to study the development of neuropathology and simulate Long COVID patients with a history of hospitalization at the acute SARS-CoV-2 infection stage. To address neuroinflammation in the mild respiratory COVID and moderate mortality COVID mouse model, we are targeting reactive microglia for therapeutic intervention, evaluating various approaches.