SARS-CoV-2 infection suppresses ACE2 function and antiviral immune response in the upper respiratory tract of infected patients

Gutierrez-Chamorro, L.; Riveira-Munoz, E.; Barrios, C.; Palau, V.; Massanella, M.; Garcia-Vidal, E.; Badia, R.; Pedreno, S.; Senserrich, J.; Rodriguez, E.; Clotet, B.; Cabrera, C.; Mitja, O.; Crespo, M.; Pascual, J.; Riera, M.; Ballana, E.

doi:10.1101/2020.11.18.388850

bioRxiv · 10.1101/2020.11.18.388850

SARS-CoV-2 infection suppresses ACE2 function and antiviral immune response in the upper respiratory tract of infected patients

Gutierrez-Chamorro, L.·Riveira-Munoz, E.·Barrios, C.·Palau, V.·Massanella, M.·Garcia-Vidal, E.·Badia, R.·Pedreno, S.·Senserrich, J.·Rodriguez, E.·Clotet, B.·Cabrera, C.·Mitja, O.·Crespo, M.·Pascual, J.·Riera, M.·Ballana, E.

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Abstract

There is an urgent need to elucidate the molecular mechanisms underlying the transmissibility and pathogenesis of SARS-CoV-2. ACE2 is a host ectopeptidase with well-described anti-inflammatory and tissue protective functions and the receptor for the virus. Understanding SARS-CoV-2-ACE2 interaction and the expression of antiviral host genes in early infection phase is crucial for fighting the pandemic. We tested the significance of soluble ACE2 enzymatic activity longitudinally in positive nasopharyngeal swabs at two time points after symptom consultation, along with gene expression profiles of ACE2, its proteases, ADAM17 and TMPRRS2, and interferon-stimulated genes (ISGs), DDX58, CXCL10 and IL-6. Soluble ACE2 activity decreased during infection course, in parallel to ACE2 gene expression. On the contrary, SARS-CoV-2 infection induced expression of the ISG genes in positive SARS-CoV-2 samples at baseline compared to negative control subjects, although this increase wanes with time. These changes positively correlated with viral load. Our results demonstrate the existence of mechanisms by which SARS-CoV-2 suppress ACE2 expression and function casting doubt on the IFN-induced upregulation of the receptor. Moreover, we show that initial intracellular viral sensing and subsequent ISG induction is also rapidly downregulated. Overall, our results offer new insights into ACE2 dynamics and inflammatory response in the human upper respiratory tract that may contribute to understand the early antiviral host response to SARS-CoV-2 infection.

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Gutierrez-Chamorro, L., Riveira-Munoz, E., Barrios, C., Palau, V., Massanella, M., Garcia-Vidal, E., Badia, R., Pedreno, S., Senserrich, J., Rodriguez, E., Clotet, B., Cabrera, C., Mitja, O., Crespo, M., Pascual, J., Riera, M., Ballana, E.. 2020-11-19. SARS-CoV-2 infection suppresses ACE2 function and antiviral immune response in the upper respiratory tract of infected patients. https://doi.org/10.1101/2020.11.18.388850

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