Is There a Link Between the Pathogenic Human Coronavirus Envelope Protein and Immunopathology? A Review of the Literature

Abstract

Since the severe acute respiratory syndrome (SARS) outbreak in 2003, human coronaviruses (hCoVs) have been identified as causative agents of severe acute respiratory tract infections. Two more hCoV outbreaks have since occurred, the most recent being SARS-CoV-2, the causative agent of coronavirus disease 2019 (COVID-19). The clinical presentation of SARS and MERS is remarkably similar to COVID-19, with hyperinflammation causing a severe form of the disease in some patients. Previous studies show that the expression of the SARS-CoV E protein is associated with the hyperinflammatory response that could culminate in acute respiratory distress syndrome (ARDS), a potentially fatal complication. This immune-mediated damage is largely caused by a cytokine storm, which is induced by significantly elevated levels of inflammatory cytokines interleukin (IL)-1β and IL-6, which are partly mediated by the expression of the SARS-CoV E protein. The interaction between the SARS-CoV E protein and the host protein, syntenin, as well as the viroporin function of SARS-CoV E, are linked to this cytokine dysregulation. This review aims to compare the clinical presentation of virulent hCoVs with a specific focus on the cause of the immunopathology. The review also proposes that inhibition of IL-1β and IL-6 in severe cases can improve patient outcome.

Keywords: COVID-19; MERS-CoV; SARS-CoV; SARS-CoV-2; envelope protein; human coronavirus; immunopathology.

FIGURE 1

A sequence comparison of the envelope (E) protein amino acid sequences for the pathogenic human coronaviruses (hCoVs). The comparison was constructed using Jalview software (v 2.11.1.0) and the important sequence features transmembrane domain (TMD) (brown), conserved cysteine (blue) and proline (red) residues, and the PDZ-binding motif (PBM) (orange) are indicated. The E protein reference amino acid sequences for SARS-CoV (P59637), MERS-CoV (K9N5R3), and SARS-CoV-2 (QHD43418.1), along with their accession IDs, were obtained from the NCBI database.

FIGURE 2

A summary of the role that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) envelope (E) protein plays in the immunopathology of severe coronavirus disease 2019 (COVID-19) cases. The E protein can induce a cytokine storm through protein-protein interaction (PPI) with the host protein syntenin and is mediated by the last four residues of the E protein which constitute the PDZ-binding motif (PBM). This activates the p38 MAPK signaling pathway, triggering the release of inflammatory cytokines. The E protein can also stimulate the release of the inflammatory cytokine interleukin (IL)-1β through its ion-channel (IC) activity. It forms a viroporin that can channel calcium ions (Ca²⁺), which activates the NLRP3 inflammasome that produces IL-1β. The resulting cytokine storm is responsible for the immune-mediated pathology often seen in severe COVID-19 cases and give rise to complications such as pulmonary edema and the acute respiratory distress syndrome (ARDS).