| Abstract |
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused more than 7 million worldwide deaths, but the mechanisms underlying its severe clinical outcomes remain elusive. Although attachment of the spike (S) protein of SARS-CoV-2 to angiotensin-converting enzyme 2 (ACE2), a pivotal step for infection, induces inflammation, the intracellular signals triggered by this interaction are unclear. Here, we found that S protein induced phosphorylation of SMAD family member 5 which was mediated by the bone morphologenetic protein (BMP) receptor activin receptor-like kinase 1 (ALK1) and BMP receptor type II. SMAD5 activation depended on the interaction of the cytoplasmic domains of ACE2 and ALK1. Notably, repetitive treatment with S protein increased the expression of immune-response genes, including interferon regulatory factor 1, interleukin-17A, and cysteine-cysteine chemokine motif ligand 20 (CCL20), all of which were blocked by an ALK inhibitor. In contrast, the S protein of human coronavirus NL63, a pathogen of acute respiratory infection with less severity than SARS-CoV-2 that also binds to ACE2, did not activate SMAD5. Because CCL20 recruits multiple immune cells positive for CC receptor 6, a specific receptor for CCL20, and was detected in broncho-alveolar lavage fluids of patients with respiratory failures by SARS-Cov-2, data suggest that SMAD5 activation by S protein augments the early immune response, leading to the severe clinical outcomes of SARS-CoV-2.
|
