The Ebola-Glycoprotein Modulates the Function of Natural Killer Cells

• Main Authors: Avishay Edri, Avishai Shemesh, Muhammed Iraqi, Omri Matalon, Michael Brusilovsky, Uzi Hadad, Olga Radinsky, Orly Gershoni-Yahalom, John M. Dye, Ofer Mandelboim, Mira Barda-Saad, Leslie Lobel, Angel Porgador
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2018-07-01
• Series: Frontiers in Immunology
• Subjects: Ebola GP; Ebola; modulation of immune system; viral evasion strategies; NKG2D; MICA
• Online Access: https://www.frontiersin.org/article/10.3389/fimmu.2018.01428/full

The Ebola virus (EBOV) uses evasion mechanisms that directly interfere with host T-cell antiviral responses. By steric shielding of human leukocyte antigen class-1, the Ebola glycoprotein (GP) blocks interaction with T-cell receptors (TCRs), thus rendering T cells unable to attack virus-infected cells. It is likely that this mechanism could promote increased natural killer (NK) cell activity against GP-expressing cells by preventing the engagement of NK inhibitory receptors; however, we found that primary human NK cells were less reactive to GP-expressing HEK293T cells. This was manifested as reduced cytokine secretion, a reduction in NK degranulation, and decreased lysis of GP-expressing target cells. We also demonstrated reduced recognition of GP-expressing cells by recombinant NKG2D and NKp30 receptors. In accordance, we showed a reduced monoclonal antibody-based staining of NKG2D and NKp30 ligands on GP-expressing target cells. Trypsin digestion of the membrane-associated GP led to a recovery of the recognition of membrane-associated NKG2D and NKp30 ligands. We further showed that membrane-associated GP did not shield recognition by KIR2DL receptors; in accordance, GP expression by target cells significantly perturbed signal transduction through activating, but not through inhibitory, receptors. Our results suggest a novel evasion mechanism employed by the EBOV to specifically avoid the NK cell immune response.