Differential proinflammatory activities of Spike proteins of SARS-CoV-2 variants of concern

Abstract

The coronavirus disease 2019 (COVID-19) pandemic turned the whole world upside down in a short time. One of the main challenges faced has been to understand COVID-19–associated life-threatening hyperinflammation, the so-called cytokine storm syndrome (CSS). We report here the proinflammatory role of Spike (S) proteins from different severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern in zebrafish. We found that wild-type/Wuhan variant S1 (S1WT) promoted neutrophil and macrophage recruitment, local and systemic hyperinflammation, emergency myelopoiesis, and hemorrhages. In addition, S1γ was more proinflammatory S1δ was less proinflammatory than S1WT, and, notably, S1β promoted delayed and long-lasting inflammation. Pharmacological inhibition of the canonical inflammasome alleviated S1-induced inflammation and emergency myelopoiesis. In contrast, genetic inhibition of angiotensin-converting enzyme 2 strengthened the proinflammatory activity of S1, and angiotensin (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.

Zebrafish models of COVID-19

“…Thus, the forced expression of full-length wild type S led to the induction of strong inflammation and generation of hemorrhages in the head of about 45% of the larvae, confirming the proinflammatory effects of wild type S in zebrafish larvae (Tyrkalska et al. 2022 ).…”

“…Our group has very recently shown that S1 domain of recombinant S protein (S1WT) can provoke local and systemic inflammation, CRS, emergency myelopoiesis, strong recruitment of the immune cells to the site of the protein injection and intracranial hemorrhages in vivo in zebrafish larvae (Tyrkalska et al. 2022 ). Notably, the injection of S1WT into the hindbrain of 48 hours post fertilization (hpf) larvae strongly induced the production of pro-inflammatory cytokines, the production of neutrophils and macrophages in response to the threat, as well as caused hemorrhages in the head of 25% of the larvae.…”

“…In particular, S1γ protein was more proinflammatory and S1δ was less proinflammatory than S1WT and, strikingly, S1β promoted delayed and long-lasting inflammation (Tyrkalska et al. 2022 ). Further, the injection of full-length RNA of wild type S into one-cell stage embryos mimicked the phenotype of the larvae injected with the recombinant Spike proteins.…”

The nasopharyngeal microbiome in COVID-19

“…Finally, and even more important, these studies did not consider the possibility that the SARS-CoV-2 positive individuals enrolled could be infected by distinct SARS-CoV-2 variants. Since it has already been described that the distinct SARS-CoV-2 variants of concern are able to elicit distinct responses in the host [ 79 , 80 ], it would not be surprising if these variants could differentially alter the nasopharyngeal microbiota. This is a particularly relevant issue to consider here, as some of these studies even state that their samples come from three different COVID-19 waves and from patients with different disease severities (Table S1) [ 66 , 67 , 70 ], which makes it very likely that they may be infected by distinct variants of the virus and, therefore, the results from the different patients enrolled in these studies would not be comparable.…”

Omicron induced distinct immune respiratory transcriptomics signatures compared to pre‐existing variants in critically ill COVID‐19 patients

“…Severe COVID-19 pneumonia results from a complex impairment of the inflammatory and immune responses against SARS-CoV-2 infection. 4 Both in vitro and in vivo animal model studies have suggested that viral variants differently modulate immunity and/or inflammation pathways, 7,14,19,20,33 possibly explaining differences in their pathogenicity and clinical expression. Differences in their transmissibility and ability to induce severe disease have been suggested by several cohort studies.…”