Direct and indirect effects of SARS-CoV-2 on the brain - a translational approach to Long COVID Syndrome

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) primarily affects the respiratory tract but can also cause neurological symptoms such as loss of smell and taste, headache or fatigue. Up to a quarter of COVID-19 patients, including those with a mild acute clinical course, develop long COVID syndrome (LCS), a complex condition with prolonged heterogeneous symptoms including fatigue, malaise, and cognitive impairment. It is not yet clear whether these persistent symptoms are due to direct or indirect effects of virus infection and whether the central nervous system (CNS) is directly involved. However, the increasing numbers of patients with LCS are raising public health concern. Therefore, more detailed studies in particular on the long-term effects of SARS-CoV-2 infection on the CNS are urgently required. Using the K18-hACE2 mouse COVID-19 model, we have shown that all virus variants apart from Omicron can be neuroinvasive and infect neurons without overt damage, but induce microglial activation and a mild non-suppurative encephalitis, suggesting a direct viral effect on the CNS; other studies also indicate a role of systemically induced neuroinflammation in LCS.The objective of the project associated with the research stay is to shed light on the potential mechanisms underlying LCS. The specific aims are to determine the transcriptomic, translational and pathological changes in the brain of SARS-CoV-2 infected mice, with a focus on the inflammatory response, but also considering the impact on the functional and metabolic state, with and without viral infection of the brain, and - in the former - before and with the presence of inflammatory cells.Transgenic (K18-hACE2) mice will be experimentally infected with SARS-CoV-2 variants (eg. Pango B, Delta, Omicron), sacrificed at different time points early and late, i.e. after clinical recovery, after infection, and subjected to an in-depth transcriptome, proteomics and neuropathological investigation on the brain. The occurrence of viral persistence as well as the effect of immunosuppression and antiviral treatments on neuroinvasion and neuroinflammation will also be determined. The results of the study will elucidate the direct and indirect effect of SARS-CoV-2 variants infection on the brain, both at an early stage after infection and after recovery from respiratory disease. They will provide insight into possible mechanisms and pathways involved in LCS and might give indications to key biomarkers that could inform future investigations in humans. The study is expected to direct future approaches towards the prevention and treatment of LCS and hence have substantial public health impact.