SARS‐CoV‐2 infection impacts carbon metabolism and depends on glutamine for replication in Syrian hamster astrocytes

Abstract

COVID‐19 causes more than million deaths worldwide. Although much is understood about the immunopathogenesis of the lung disease, a lot remains to be known on the neurological impact of COVID‐19. Here we evaluated immunometabolic changes using astrocytes in vitro and dissected brain areas of SARS‐CoV‐2 infected Syrian hamsters. We show that SARS‐CoV‐2 alters proteins of carbon metabolism, glycolysis, and synaptic transmission, many of which are altered in neurological diseases. Real‐time respirometry evidenced hyperactivation of glycolysis, further confirmed by metabolomics, with intense consumption of glucose, pyruvate, glutamine, and alpha ketoglutarate. Consistent with glutamine reduction, the blockade of glutaminolysis impaired viral replication and inflammatory response in vitro . SARS‐CoV‐2 was detected in vivo in hippocampus, cortex, and olfactory bulb of intranasally infected animals. Our data evidence an imbalance in important metabolic molecules and neurotransmitters in infected astrocytes. We suggest this may correlate with the neurological impairment observed during COVID‐19, as memory loss, confusion, and cognitive impairment.

Neuropilin-1 Mediates SARS-CoV-2 Infection of Astrocytes in Brain Organoids, Inducing Inflammation Leading to Dysfunction and Death of Neurons

“…Abnormal astrocyte function impairs neuronal survival and promotes neurodegeneration ( 22 , 23 ). Astrocytes from both hamsters and brain organoids have been shown to be susceptible to SARS-CoV-2 infection ( 15 , 24 , 25 ). Given the essential role of astrocytes in neuronal health and synapse function, it is possible that the neurological symptoms of COVID-19 result in part from the direct infection of astrocytes by SARS-CoV-2.…”

Immunometabolic Signature during Respiratory Viral Infection: A Potential Target for Host-Directed Therapies

“…It is clear now that different viruses, e.g., influenza virus, can infect the CNS and cause neurological disorders [ 149 ]. However, with the current COVID-19 pandemic, much more attention has been given to viruses that are known to be non-neurotropic, that is, their primary site of infection is not the brain, but yet are “neuropathogenic”, which may lead to neurological abnormalities and psychiatric disorders [ 148 , 150 , 151 , 152 ]. Interestingly, some speculations about some kind of viral etiology behind neurological disorders such as Parkinson’s disease, acute disseminated encephalomyelitis, and multiple sclerosis have gained attention as coronaviruses, such as HCoV-229E and HCoV-OC43, have been detected in patients’ brains [ 153 , 154 ].…”

Direct and indirect impact of SARS-CoV-2 on the brain

“…It is worth mentioning that wild type mice are not permissive to SARS-CoV-2 infection due to structural differences on ACE-2, although the use of the Variant of Concern (VOC) Delta B1.617.2 (Yang et al 2023 ), or a mouse adapted strain (MA10) (Amruta et al 2022 ) had indicated otherwise. For this reason, most in vitro studies used primary cells either from K18-ACE-2 transgenic mice, hamsters (Rothan et al 2022 ; de Oliveira et al 2022 ) or wild-type animals pre-treated with an adenovirus (AAV-hACE-2) as a vector to induce the expression of hACE-2 (Song et al 2021b ; Monje and Iwasaki 2022 ). Other studies also used human-derived induced-pluripotent stem cells (iPSCs) as well as brain organoids (Ramani et al 2020 , 2021 ; Jacob et al 2020 ; Song et al 2021b ; Samudyata et al 2022 ; Kong et al 2022 ), which are useful tools for the study of many aspects of brain development, function, metabolism and has already been used for the studies of other viral infection, including ZIKA virus (Cugola et al 2016 ), dengue virus, influenza virus and also SARS-CoV-2, as reviewed (Harschnitz and Studer 2021 ).…”

“…Many different animal models were established to investigate the biology of SARS-CoV-2 in vivo; from zebrafish (Ventura Fernandes et al 2022 ; Kraus et al 2022 ), mice (Kumari et al 2021 ; Rhea et al 2021 ) and hamsters (Rosenke et al 2020 ; Zazhytska et al 2022 ; de Oliveira et al 2022 ) to ferrets (Kim et al 2022 ) and macaques (Rutkai et al 2022 ; Beckman et al 2022 ), as reviewed (Muñoz-Fontela et al 2020 ).…”

“…Most models used the intranasal inoculation of viable SARS-CoV-2 viral particles either in K18- hACE-2 transgenic mice or after the delivery of an adenovirus carrying the hACE-2 gene (AAV-K18–hACE-2). Hamsters and Rhesus monkeys are also powerful tool to investigate COVID-19, not only because they are naturally susceptible to infection (Imai et al 2020 ; Song et al 2021c ; de Oliveira et al 2022 ) but also because they develop many similar features to the human disease. These models have given evidence supporting both the presence (Kumari et al 2021 ; Song et al 2021b ; Jiao et al 2021 ; de Oliveira et al 2022 ) and the absence (Fernández-Castañeda et al 2022 ; Soung) of neuroinfection.…”