ABSTRACT: Coronaviruses belong to a well-known family of enveloped RNA viruses and the causative agent of the common cold. Although the seasonal coronaviruses do not pose a threat to human life, three members of this family, i.e., SARS-CoV, MERS-CoV and recently, SARS-CoV2, may cause severe acute respiratory syndrome that may lead to death. Unfortunately, COVID-19 has already caused more than 4,4 million deaths worldwide. Although much is better understood about the immunopathogenesis of the lung disease, important information about systemic disease is still missing, mainly concerning neurological parameters. In this context, we sought to evaluate immunometabolic changes using in vitro and in vivo models of hamsters infected with SARS-CoV2. Here show that, besides infecting and replicating in glial cells, SARS-CoV2 induces important changes in protein expression and metabolic pathways, specially involved in carbon metabolism, glycolysis, and mitochondrial respiration. Interestingly, many of the differentially expressed proteins during SARS-CoV2 infection overlapped with proteins correlated with neurological diseases, such as Parkinsons's Disease, multiple sclerosis, amyotrophic lateral sclerosis and Huntington's disease. Metabolic analysis by high resolution real-time respirometry evidenced hyperactivation of glycolysis and mitochondrial respiration, which was confirmed by metabolomics. Brain infection with SARS-CoV2 was confirmed in vivo as hippocampus, cortex and olfactory bulb of infected hamsters were positive for viral genome both at 4 and 7 days post-infection. Unexpectedly, we observed that glutamine was significantly reduced in mixed glial cells infected with SARS-CoV2 and that the blockade of glutaminolysis significantly reduced viral replication and pro-inflammatory response. Altogether, our data confirms the infection of brain cells by SARS-CoV2 but, most importantly, there is an important change in overall protein expression profile, mostly of proteins related to metabolic pathways. This may suggest that some of the neurological impairments observed during COVID-19, as the brain fog and cognitive impairment, may rely on altered protein expression and unbalanced glutamine/glutamate levels, whose importance for adequate brain function is unquestionable.
Victor Corasolla Carregari 
