Correlating the ability of VP24 protein from Ebola and Marburg viruses to bind human karyopherin to their immune suppression mechanism and pathogenicity using computational methods

Abstract

Immune response suppression is crucial for viral invasion. The protein VP24 is pivotal in achieving this in Ebola, although interestingly the mechanism of immune suppression is different in the closely related Marburg virus. Here, we illustrate that a possible molecular basis for this diffrence emanates from two alpha helical structures (α5 and α6) in VP24 involved in binding human karyopherin (KPNA) (PDBid:4U2X), wherein the Ebola and Marburg viruses have distinctly different charged properties in α5. α6 is absent in Marburg, and has a different hydrophobic moment in the Reston Ebola (REBOV) species, which is surprisingly non-pathogenic in humans. Based on the hypothesis that REBOV is not immunosuppressive, which is in turn is due to its inability to bind KPNA, we show by docking KPNA to the REBOV VP24 that the single amino acid substitution R140S is responsible for this difference between REBOV and Zaire Ebola strains. Such a scenario of getting a virulent REBOV through a single mutation is particularly worrisome, since the REBOV, once found only in monkeys, has been recently detected in pigs. We also reiterate the potential of using these helices as potential epitopes for generating protective antibodies against Ebola.