Increased mTOR signaling, impaired autophagic flux and cell-to-cell viral transmission are hallmarks of SARS-CoV-2 infection.

Celeste Maktura, G.; Luscher Dias, T.; Pereira Zambalde, E.; Brenha, B.; R. Amorim, M.; Nunes Santos, L.; Buscaratti, L.; Gabriel de Angeli Elston, J.; Mara, C.; Camargo Silva Mancini, M.; Carolina Betim Pavan, I.; A. Toledo-Teixeira, D.; Bispo-dos-Santos, K.; L. Parise, P.; Primon Muraro, S.; Fabiano de Souza, G.; Paula Morelli, A.; Guilherme Salvino da Silva, L.; Maia Santos de Castro, I.; Oliveira Barbosa, G.; G. Ludwig, R.; L. Knittel, T.; D. Saccon, T.; A. Mori, M.; Granja, F.; F. Carvalho, H.; Lamberti Pinto da Silva, L.; I. Nakaya, H.; Luiz Proenca-Modena, J.; Moreira Simabuco, F.; Marq

doi:10.1101/2021.10.13.464225

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bioRxiv · 10.1101/2021.10.13.464225

Increased mTOR signaling, impaired autophagic flux and cell-to-cell viral transmission are hallmarks of SARS-CoV-2 infection.

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Abstract

The COVID-19 disease caued by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has two characteristics that distinguish it from other viral infections. It affects more severely people with pre-existing comorbidities and viral load peaks prior to the onset of the symptoms. Investigating factors that could contribute to these characteristics, we found increased mTOR signaling and suppressed genes related to autophagy, lysosome, and vesicle fusion in Vero E6 cells infected with SARS-CoV-2. Transcriptomic data mining of bronchoalveolar epithelial cells from severe COVID-19 patients revealed that COVID-19 severity is associated with increased expression of genes related to mTOR signaling and decreased expression of genes related to autophagy, lysosome function, and vesicle fusion. SARS-CoV-2 infection in Vero E6 cells also resulted in virus retention inside the cells and trafficking of virus-bearing vesicles between neighboring cells. Our findings support a scenario where SARS-CoV-2 benefits from compromised autophagic flux and inhibited exocytosis in individuals with chronic hyperactivation of mTOR signaling, which might relate to undetectable proliferation and evasion of the immune system.

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Celeste Maktura, G., Luscher Dias, T., Pereira Zambalde, E., Brenha, B., R. Amorim, M., Nunes Santos, L., Buscaratti, L., Gabriel de Angeli Elston, J., Mara, C., Camargo Silva Mancini, M., Carolina Betim Pavan, I., A. Toledo-Teixeira, D., Bispo-dos-Santos, K., L. Parise, P., Primon Muraro, S., Fabiano de Souza, G., Paula Morelli, A., Guilherme Salvino da Silva, L., Maia Santos de Castro, I., Oliveira Barbosa, G., G. Ludwig, R., L. Knittel, T., D. Saccon, T., A. Mori, M., Granja, F., F. Carvalho, H., Lamberti Pinto da Silva, L., I. Nakaya, H., Luiz Proenca-Modena, J., Moreira Simabuco, F., Marq. 2021-10-14. Increased mTOR signaling, impaired autophagic flux and cell-to-cell viral transmission are hallmarks of SARS-CoV-2 infection.. https://doi.org/10.1101/2021.10.13.464225

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