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

The COVID-19 disease caused 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. Investigat...

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Published in:	bioRxiv 2021-10
Main Authors:	Grazielle Celeste Maktura, Thomaz Luscher Dias, Erika Pereira Zambalde, Brenha, Bianca, Amorim, Mariene R, Luana Nunes Santos, Lucas Buscaratti, Joao Gabriel De Angeli Elston, Mara, Cynthia, Mariana Camargo Silva Mancini, Isadora Carolina Betim Pavan, Toledo-Teixeira, Daniel A, Bispo-Dos-Santos, Karina, Parise, Pierina L, Stefanie Primon Muraro, Gabriela Fabiano De Souza, Ana Paula Morelli, Luiz Guilherme Salvino Da Silva, Icaro Maia Santos De Castro, Guilherme Oliveira Barbosa, Ludwig, Raissa G, Knittel, Thiago L, Saccon, Tatiana D, Mori, Marcelo A, Granja, Fabiana, Carvalho, Hernandes F, Luis Lamberti Pinto Da Silva, Nakaya, Helder I, Proenca-Modena, Jose Luiz, Fernando Moreira Simabuco, Marques-Souza, Henrique
Format:	Article
Language:	eng
Subjects:	Autophagy Bronchus Cell fusion Coronaviruses COVID-19 Disease transmission Epithelial cells Exocytosis Immune system Phagocytosis Severe acute respiratory syndrome coronavirus 2 TOR protein Vesicle fusion Viral infections
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Summary:	The COVID-19 disease caused 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 au-tophagy, lysosome function, and vesicle fusion. SARS-CoV-2 infection in Vero E6 cells also re-sulted 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. Competing Interest Statement The authors have declared no competing interest.