Ebola Pathogenic Genes

In general, filoviruses possess a noninfectious, negativesense, single-stranded, nonsegmented RNA genome within a lipid envelope. The cellular receptors required for cell infection are not definitively clarified. The Ebola virus genome is 19kb long and includes seven open reading frames encoding structural proteins [the glycoprotein (GP), the nucleoprotein (NP), and the matrix proteins VP24 and VP40], nonstructural proteins (VP30 and VP35), and the viral polymerase (Figure 2). Additionally, the GP open reading frame of Ebola virus, through transcriptional editing, generates two different gene products: a full-length 150- to 170-kDa protein (GP) that inserts into the viral membrane and a soluble 60- to 70-kDa protein (sGP), that is secreted from infected cells. The Ebola glycoproteins, GP and sGP, share approximately 300 amino-terminal amino acids, but contain an additional 380 and 70 carboxy-terminal amino acids, respectively. Both are thought to play important roles in viral pathogenesis [6].

Ebola Envelope Glycoprotein (GP)

The Ebola GP forms a trimeric complex expressed on the viral envelope and is responsible for receptor binding and viral fusion with host cells. The affinity of Ebola for endothelial cells appears to be due, in part, to GP's preferential binding to these cells [7]. In addition to mediating host cell binding, GP also appears to harbor cytopathic effects when expressed in different cell types in vitro. Specifically, GP expression in cultured human endothelial and epithelial cells causes cell rounding and detachment. These effects correlate with the downregulation of expression of important cell-surface molecules involved in matrix adhesion such as integrins [8]. Interestingly, GP from the Ebola Zaire strain—which is lethal in both humans and nonhuman primates—has the most robust activity in this cell culture assay. Ebola Zaire GP also induces severe damage and increased permeability of the endothelial cell lining in blood vessel explants derived from both human and nonhuman primates [9]. Conversely, GP encoded by the Ebola Reston strain—which is lethal only in nonhuman primates—induces similar effects only in nonhuman primate vessels. This remarkable congruence between Ebola GP cytotoxicity in vitro and Ebola strain pathogenicity in vivo suggests that the GP may be an important viral determinant of endothelial cell toxicity in Ebola infection.

Ebola Secreted Glycoprotein

Two functions have been hypothesized for the secretory glycoprotein (sGP). This dimeric, nonstructural protein has the ability to inhibit the neutralizing activity of anti-GP antiserum, suggesting that it may act as a decoy to adsorb neutralizing antibodies against GP. This might explain why GP-specific antibodies are not usually detected in patient sera during acute infection, while antibodies to the other major viral proteins are readily found. sGP may also play an important role in immune evasion. sGP has been reported to bind to human neutrophils, interfering with the physical and functional interaction between CD 16b and CR3, thereby impairing early steps in neutrophil activation that ordinarily contribute to virus clearance. This may help explain why Ebola virus spreads so rapidly through the body without eliciting a proper immune response in acutely infected patients.

Other Ebola Proteins

Several of the other Ebola proteins have been shown to be essential for efficient viral infection, replication, and pathogenesis. The Ebola virus nucleoprotein, VP35, VP30, and RNA polymerase are all required for RNA replication and transcription. Recent data also indicate that VP35 can act as a type 1 IFN antagonist, suggesting that this protein may also be required for full Ebola virulence. Viral protein 40 (VP40) is another suspected cytotoxic protein, which induces particle formation when expressed in mammalian cells. This process most likely requires cellular WW-domain-containing proteins that interact with the amino-terminal proline-rich region of VP40. It was also demonstrated that VP40 interacts with an ubiquitin ligase. The biological significance of this interaction is still unclear, although it may be involved in assembly and budding of filoviruses.

Ultimately, the key to fully understanding the relative contribution of Ebola genes to VHF will rely on the development of model systems to safely and effectively examine this virus in vitro and in vivo.

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