Factors affecting RIG-I-Like receptors activation - New research direction for viral hemorrhagic fevers

Abstract

Viral hemorrhagic fever (VHF) is a term referring to a group of life-threatening infections caused by several virus families (Arenaviridae, Bunyaviridae, Filoviridae and Flaviviridae). Depending on the virus, the infection can be mild and can be also characterized by an acute course with fever accompanied by hypervolemia and coagulopathy, resulting in bleeding and shock. It has been suggested that the course of the disease is strongly influenced by the activation of signaling pathways leading to RIG-I-like receptor-dependent interferon production. RIG-I-like receptors (RLRs) are one of two major receptor families that detect viral nucleic acid. RLR receptor activation is influenced by a number of factors that may have a key role in the differences that occur during the antiviral immune response in VHF. In the present study, we collected data on RLR receptors in viral hemorrhagic fevers and described factors that may influence the activation of the antiviral response. RLR receptors seem to be a good target for VHF research, which may contribute to better therapeutic and diagnostic strategies. However, due to the difficulty of conducting such studies in humans, we suggest using Lagovirus europaeus as an animal model for VHF.

Keywords: Lagovirus europaeus; MAVS; RLR; VHF; immune activation; interferon; signaling; signaling pathways.

Figure 1

Schematic structure of RIG-I-like receptors.

Figure 2

Diagram showing activation of the immune response leading to RLR receptor-dependent production of type I interferon and pro-inflammatory cytokines (CARD, caspase activation and recruitment domain; RD, repressor/regulatory domain; MDA5, melanoma differentiation associated gene 5; RIG-I, retinoic acid-inducible gene-I; MAVS, mitochondrial antiviral signaling protein; TRADD, TNFR1-associated death domain; TRAF3, TNF receptor-associated factor 3; RIP1, receptor interacting protein 1; FADD, Fas-associated death domain; NEMO, NF-κB essential modulator; NF-κB essential modulator; TBK1, TANK-binding kinase 1; IKK, IκB kinase; IRF, IFN-gene regulatory factor; NF-κB –nuclear factor κB; IFN, interferon).

Figure 3

Diagram showing relationship between RIG-I-like receptors, their factors and viral hemorrhagic fevers (JUNV, Junín virus; LASV, Lassa virus; SFTSV, severe fever with thrombocytopenia syndrome virus; CCHFV, Crimean-Congo hemorrhagic fever virus; HTNV, Hantaan virus; RVFV, Rift Valley Fever Virus; DENV, dengue virus; ATMUV, avian Tembus virus; EBOV, Ebola virus; MARV, Marburg virus; RLRs, RIG-I-like receptors).