A zebrafish model of COVID-19-associated cytokine storm syndrome reveals differential proinflammatory activities of Spike proteins of SARS-CoV-2 variants of concern.

The sudden and unexpected appearance of the COVID-19 pandemic turned the whole world upside down in a very short time. One of the main challenges faced has been to understand COVID-19 patient heterogeneity, as a minority develop life-threatening hyperinflammation, the so-called cytokine storm syndrome (CSS). Using the unique advantages of the zebrafish model we report here the proinflammatory role of Spike (S) proteins from different SARS-CoV-2 variants of concern after injection into the hindbrain ventricle, a cavity filled with cerebrospinal fluid to which immune cells can be easily recruited and that mimics the alveolar environment of the human lung. We found that wild type/Wuhan variant S1 (S1WT) protein promoted neutrophil and macrophage recruitment, local and systemic hyperinflammation, emergency myelopoiesis, and hemorrhages. In addition, S1{gamma} protein was more proinflammatory and S1{delta} was less proinflammatory than S1WT and, strikingly, S1{beta} promoted delayed and long-lasting inflammation. Pharmacological inhibition of the canonical inflammasome robustly alleviated S1 protein-induced inflammation and emergency myelopoiesis. In contrast, genetic inhibition of angiotensin-converting enzyme 2 strengthened the proinflammatory activity of S1, and the administration of angiopoietin (1-7) fully rescued S1-induced hyperinflammation and hemorrhages. These results shed light into the mechanisms orchestrating the COVID-19-associated CSS and the host immune response to different SARS-CoV-2 S protein variants. HighlightsO_LIS proteins of SARS-CoV-2 promote hyperinflammation, neutrophilia, monocytosis and hemorrhages in zebrafish. C_LIO_LIS protein effects in zebrafish are mediated via the canonical inflammasome and the Ace2/Angiopoietin (1-7) axis. C_LIO_LIDelta S1 is less proinflammatory than wild type S1 and fails to induce emergency myelopoiesis in zebrafish. C_LIO_LINaive and primed human white blood cells are unable to respond to S proteins. C_LI