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

• Published in: Journal of neurochemistry 2022-10, Vol.163 (2), p.113-132
• Main Authors: Oliveira, Lilian Gomes, Souza Angelo, Yan, Yamamoto, Pedro, Carregari, Victor Corasolla, Crunfli, Fernanda, Reis‐de‐Oliveira, Guilherme, Costa, Lícia, Vendramini, Pedro Henrique, Duque, Érica Almeida, Santos, Nilton Barreto, Firmino, Egidi Mayara, Paiva, Isadora Marques, Almeida, Glaucia Maria, Sebollela, Adriano, Polonio, Carolina Manganeli, Zanluqui, Nagela Ghabdan, Oliveira, Marília Garcia, Silva, Patrick, Davanzo, Gustavo Gastão, Ayupe, Marina Caçador, Salgado, Caio Loureiro, Souza Filho, Antônio Francisco, Araújo, Marcelo Valdemir, Silva‐Pereira, Taiana Tainá, Almeida Campos, Angélica Cristine, Góes, Luiz Gustavo Bentim, Passos Cunha, Marielton, Caldini, Elia Garcia, D'Império Lima, Maria Regina, Fonseca, Denise Morais, Sá Guimarães, Ana Márcia, Minoprio, Paola Camargo, Munhoz, Carolina Demarchi, Mori, Cláudia Madalena Cabrera, Moraes‐Vieira, Pedro Manoel, Cunha, Thiago Mattar, Martins‐de‐Souza, Daniel, Peron, Jean Pierre Schatzmann
• Format: Article
• Language: English
• Subjects: Astrocytes; Carbon; Cognitive ability; Cortex (olfactory); COVID-19; Glutamine; Glycolysis; Hamsters; Immunopathogenesis; Impairment; Inflammation; Inflammatory response; Ketoglutaric acid; Life Sciences; Lung diseases; Metabolism; Metabolomics; Neurological complications; Neurological diseases; neuropathology; Neurotransmitters; Olfactory bulb; Original; proteomics; Pyruvic acid; Replication; Respirometry; SARS‐CoV2; Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Synaptic transmission; Viral diseases
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.15679

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. Intranasal in vivo infection of Syrian hamster and in vitro infection of astrocytes by SARS‐CoV‐2 induces increased expression of pro‐inflammatory cytokines and interferon‐stimulated genes. Astrocytes infected in vitro also demonstrated dysregulated metabolic pathways with important decrease of intermediates and substrates from tricarboxylic cycle (TCA). Importantly, the blockage of glutaminolysis was critical for the maintenance of viral replication. Protein analysis evidenced that SARS‐CoV‐2 infection both in vitro and in vivo results in enriched pathways associated with neurological diseases and alterations in inflammatory and metabolic pathways which are also found in single‐cell analysis of COVID‐19 patients' brains.