ID: 71: Ebola and Marburg virus proteins effectively interfere with the activation of TLR and RIG-I signaling pathways

Abstract

Ebola (EBOV) and Marburg (MARV) filoviruses have caused several outbreaks in Africa. The latest Ebola virus outbreak which started in 2014 in Guinea progressed to a large epidemic which spread to several countries with ca 27 500 cases and 11 200 deaths (by June 2015). Basic knowledge in filovirus – host cell interactions should be increased in order to develop better modalities of treatment for these highly lethal viral pathogens. We have cloned six EBOV (strain from Sierra Leone, June 2014) and six MARV (strain from Uganda, October/November 2012) genes to be expressed in transient mammalian expression system. The effect of Ebola and Marburg virus proteins on Toll-like receptors (TLRs) and RIG-I signaling pathways was analyzed in detail by co-transfecting IFN-lambda1, IFN-beta and IFN-alpha promoter Luc-reporters and the expression constructs for various signaling molecules (MyD88, TRIF, MAVS, IKK-e, TBK1, NF-kB, IRF3, IRF7) and EBOV and MARV genes into primary human leukocytes and various cell lines. At least two EBOV proteins were found to interfere with the activation of RIG-I-mediated innate immune responses. VP35 interfered with the RNA induced activation of the RIG-I. VP24, instead, blocked the whole RIG-I pathway by interfering with IFN gene expression induced by all signaling component. VP24 targeted IRF3, whose nuclear accumulation and transcriptional activity for IFN genes was strongly inhibited. The data provides detailed information on the molecular mechanisms how filoviruses interfere with the activation of host IFN-mediated antiviral responses in human cell systems.