Conserved differences in protein sequence determine the human pathogenicity of Ebolaviruses

Abstract

Reston viruses are the only Ebolaviruses that are not pathogenic in humans. We analyzed 196 Ebolavirus genomes and identified specificity determining positions (SDPs) in all nine Ebolavirus proteins that distinguish Reston viruses from the four human pathogenic Ebolaviruses. A subset of these SDPs will explain the differences in human pathogenicity between Reston and the other four ebolavirus species. Structural analysis was performed to identify those SDPs that are likely to have a functional effect. This analysis revealed novel functional insights in particular for Ebolavirus proteins VP40 and VP24. The VP40 SDP P85T interferes with VP40 function by altering octamer formation. The VP40 SDP Q245P affects the structure and hydrophobic core of the protein and consequently protein function. Three VP24 SDPs (T131S, M136L, Q139R) are likely to impair VP24 binding to human karyopherin alpha5 (KPNA5) and therefore inhibition of interferon signaling. Since VP24 is critical for Ebolavirus adaptation to novel hosts, and only a few SDPs distinguish Reston virus VP24 from VP24 of other Ebolaviruses, human pathogenic Reston viruses may emerge. This is of concern since Reston viruses circulate in domestic pigs and can infect humans, possibly via airborne transmission.

Risks Posed by Reston, the Forgotten Ebolavirus

“…EBOV GP contains a mucin-like domain that increases blood vesicle permeability by downregulating the expression of integrin β1 and other cell adhesion molecules (53–55). RESTV GP has several conserved SDPs (R325G, H354L, Q403P, S418E, T448P) and was found to have a significantly weaker influence in downregulating integrin β1 expression, compared to EBOV GP (46, 55). When it was examined in vivo , it was seen that the presence of the RESTV GP attenuated EBOV pathogenicity, whereas the reverse genetic conversion of RESTV GP to EBOV GP was not sufficient to confer a pathogenic phenotype on RESTV, indicating that other proteins are involved in the regulation of Ebolavirus pathogenicity (38, 42, 55).…”

“…Several of these SDPs were located on protein surfaces, suggesting their possible involvement in molecular interactions (46). While the VP24 sequence identity between EBOV and RESTV is 80%, only 9 of 251 residues were identified as SDPs, possibly contributing to RESTV’s lack of pathogenicity in humans (15).…”

“…This supports the hypothesis that RESTV VP24 may be less effective at karyopherin binding and suppressing the interferon response. In addition, another SDP in RESTV VP24 results in the loss of hydrogen bonding between T226 and D48, potentially impacting protein stability and function (46). However, the SDPs were not restricted to VP24 and many SDPs were found in other protein interfaces that may affect interactions and stability (Table 1).…”

“…RESTV VP35 has 65% sequence identity with EBOV VP35 and shows 19 SDPs (46–49). Although, it was found that both RESTV and EBOV VP35 molecules were able to inhibit IRF-3 activation, blocking the IRF3-dependent transcription of ISGs 54 and 56.…”

Interplay Among Constitutes of Ebola Virus: Nucleoprotein, Polymerase L, Viral Proteins

“…71 Several possible key di®erences on L have been proposed by comparative analysis between Zaire and Reston or other ebola species. 31,48,72 We mapped out the position of certain key residues: L283V, Y312F, A326S, T330D, S343Y, E350D, T361S, L365F in the binding core with VP35, and R654H, E689S, D759G in the Rdrp domain (listed in Table S2) on 3D model of its protein domain (Fig. 4).…”