title: Implication of a retrovirus-like glycoprotein peptide in the immunopathogenesis of Ebola and Marburg viruses.
abstract: Ebola and Marburg viruses can cause hemorrhagic fever (HF) outbreaks with high mortality in primates. Whereas Marburg (MARV), Ebola Zaire (ZEBOV), and Ebola Sudan (SEBOV) viruses are pathogenic in humans, apes, and monkeys, Ebola Reston (REBOV) is pathogenic only in monkeys. Early immunosuppression may contribute to pathogenesis by facilitating viral replication. Lymphocyte depletion, intravascular apoptosis, and cytokine dysregulation are prominent in fatal cases. Here we functionally characterize a 17 amino acid domain in filoviral glycoproteins that resembles an immunosuppressive motif in retroviral envelope proteins. Activated human or rhesus peripheral blood mononuclear cells (PBMC) were exposed to inactivated ZEBOV or a panel of 17mer peptides representing all sequenced strains of filoviruses, then analyzed for CD4+ and CD8+ T cell activation, apoptosis, and cytokine expression. Exposure of human and rhesus PBMC to ZEBOV, SEBOV, or MARV peptides or inactivated ZEBOV resulted in decreased expression of activation markers on CD4 and CD8 cells; CD4 and CD8 cell apoptosis as early as 12 h postexposure; inhibition of CD4 and CD8 cell cycle progression; decreased interleukin (IL)-2, IFN-gamma, and IL12-p40 expression; and increased IL-10 expression. In contrast, only rhesus T cells were sensitive to REBOV peptides. These findings are consistent with the observation that REBOV is not pathogenic in humans and have implications for understanding the pathogenesis of filoviral HF.
authors.affiliation: Jerome L. and Dawn Greene Infectious Disease Laboratory, Mailman School of Public Health, Columbia University, 722 West 168th St., New York, NY 10032, USA.
authors.forename: Kavitha
authors.initials: K
authors.lastname: Yaddanapudi
authors.forename: Gustavo
authors.initials: G
authors.lastname: Palacios
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Towner
authors.forename: Ivy
authors.initials: I
authors.lastname: Chen
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Sariol
authors.forename: Stuart T
authors.initials: ST
authors.lastname: Nichol
authors.forename: W Ian
authors.initials: WI
authors.lastname: Lipkin
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004306:Dose-Response Relationship, Immunologic; D029043:Ebolavirus / Q000378:metabolism*; D006023:Glycoproteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008253:Macaca mulatta; D029024:Marburgvirus / Q000378:metabolism*; D014759:Viral Envelope Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D016207:Cytokines; D006023:Glycoproteins; D014759:Viral Envelope Proteins