title: Ebolavirus delta-peptide immunoadhesins inhibit marburgvirus and ebolavirus cell entry.
abstract: With the exception of Reston and Lloviu viruses, filoviruses (marburgviruses, ebolaviruses, and "cuevaviruses") cause severe viral hemorrhagic fevers in humans. Filoviruses use a class I fusion protein, GP(1,2), to bind to an unknown, but shared, cell surface receptor to initiate virus-cell fusion. In addition to GP(1,2), ebolaviruses and cuevaviruses, but not marburgviruses, express two secreted glycoproteins, soluble GP (sGP) and small soluble GP (ssGP). All three glycoproteins have identical N termini that include the receptor-binding region (RBR) but differ in their C termini. We evaluated the effect of the secreted ebolavirus glycoproteins on marburgvirus and ebolavirus cell entry, using Fc-tagged recombinant proteins. Neither sGP-Fc nor ssGP-Fc bound to filovirus-permissive cells or inhibited GP(1,2)-mediated cell entry of pseudotyped retroviruses. Surprisingly, several Fc-tagged Δ-peptides, which are small C-terminal cleavage products of sGP secreted by ebolavirus-infected cells, inhibited entry of retroviruses pseudotyped with Marburg virus GP(1,2), as well as Marburg virus and Ebola virus infection in a dose-dependent manner and at low molarity despite absence of sequence similarity to filovirus RBRs. Fc-tagged Δ-peptides from three ebolaviruses (Ebola virus, Sudan virus, and Taï Forest virus) inhibited GP(1,2)-mediated entry and infection of viruses comparably to or better than the Fc-tagged RBRs, whereas the Δ-peptide-Fc of an ebolavirus nonpathogenic for humans (Reston virus) and that of an ebolavirus with lower lethality for humans (Bundibugyo virus) had little effect. These data indicate that Δ-peptides are functional components of ebolavirus proteomes. They join cathepsins and integrins as novel modulators of filovirus cell entry, might play important roles in pathogenesis, and could be exploited for the synthesis of powerful new antivirals.
authors.affiliation: U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Maryland 21702, USA.
authors.forename: Sheli R
authors.initials: SR
authors.lastname: Radoshitzky
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Warfield
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Chi
authors.forename: Lian
authors.initials: L
authors.lastname: Dong
authors.forename: Krishna
authors.initials: K
authors.lastname: Kota
authors.forename: Steven B
authors.initials: SB
authors.lastname: Bradfute
authors.forename: Jacqueline D
authors.initials: JD
authors.lastname: Gearhart
authors.forename: Cary
authors.initials: C
authors.lastname: Retterer
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Kranzusch
authors.forename: John N
authors.initials: JN
authors.lastname: Misasi
authors.forename: Marc A
authors.initials: MA
authors.lastname: Hogenbirk
authors.forename: Victoria
authors.initials: V
authors.lastname: Wahl-Jensen
authors.forename: Viktor E
authors.initials: VE
authors.lastname: Volchkov
authors.forename: James M
authors.initials: JM
authors.lastname: Cunningham
authors.forename: Peter B
authors.initials: PB
authors.lastname: Jahrling
authors.forename: M Javad
authors.initials: MJ
authors.lastname: Aman
authors.forename: Sina
authors.initials: S
authors.lastname: Bavari
authors.forename: Michael
authors.initials: M
authors.lastname: Farzan
authors.forename: Jens H
authors.initials: JH
authors.lastname: Kuhn
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism*; D001688:Biological Products / Q000378:metabolism; D002460:Cell Line; D029043:Ebolavirus / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000378:metabolism*; D029024:Marburgvirus / Q000187:drug effects* / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D053586:Virus Internalization / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D001688:Biological Products; D007141:Immunoglobulin Fc Fragments; D011993:Recombinant Fusion Proteins; D014764:Viral Proteins