Ebola Virus Delta Peptide Is a Viroporin

Abstract

The Ebola virus (EBOV) genome encodes a partly conserved 40-residue nonstructural polypeptide, called the delta peptide, that is produced in abundance during Ebola virus disease (EVD). The function of the delta peptide is unknown, but sequence analysis has suggested that delta peptide could be a viroporin, belonging to a diverse family of membrane-permeabilizing small polypeptides involved in replication and pathogenesis of numerous viruses. Full-length and conserved C-terminal delta peptide fragments permeabilize the plasma membranes of nucleated cells of rodent, dog, monkey, and human origin; increase ion permeability across confluent cell monolayers; and permeabilize synthetic lipid bilayers. Permeabilization activity is completely dependent on the disulfide bond between the two conserved cysteines. The conserved C-terminal portion of the peptide is biochemically stable in human serum, and most serum-stable fragments have full activity. Taken together, the evidence strongly suggests that Ebola virus delta peptide is a viroporin and that it may be a novel, targetable aspect of Ebola virus disease pathology.IMPORTANCE During the unparalleled West African outbreak of Ebola virus disease (EVD) that began in late 2013, the lack of effective countermeasures resulted in chains of serial infection and a high mortality rate among infected patients. A better understanding of disease pathology is desperately needed to develop better countermeasures. We show here that the Ebola virus delta peptide, a conserved nonstructural protein produced in large quantities by infected cells, has the characteristics of a viroporin. This information suggests a critical role for the delta peptide in Ebola virus disease pathology and as a possible target for novel countermeasures.

Antimicrobial peptides are degraded by the cytosolic proteases of human erythrocytes

“…Disulfide crosslinking also protects peptides from degradation (46). For example, we recently reported serum degradation experiments on a disulfide-crosslinked Ebola virus peptide with two conserved cysteine residues and observed nearly complete protection of the crosslinked core peptide after 24 hours (47). Similarly, one of the largest naturally-occurring AMP families, the defensins, are characterized by their multiple conserved cysteine residues and compact, disulfide crosslinked structures (48) and are probably protease resistant.…”

Ebolaviruses: New roles for old proteins

“…In addition, the sGP cleavage product, Δ-peptide, may play a role in EBOV pathogenicity by acting as a viroporin [ 91 ]. Δ-peptide is able to form pores in the plasma membrane of mammalian cells, increasing ion permeability and causing cytotoxicity [ 92 ]. However, it is not known if the Δ-peptide can be released from cells or if its induction of cytotoxicity is limited to within the infected cell.…”

The Mechanism of Membrane Permeabilization by Peptides: Still an Enigma

“…There are also bacterial and fungal peptides that act either on other microbe membranes (6,7) or on eukaryotic host cell membranes (8). There are viral peptides that can act on bacterial membranes (9) or eukaryotic host membranes (10,11). Finally, insects, arachnids, and some vertebrates produce complex venoms or toxin delivery systems that can include membrane permeabilizing peptides (12).…”