Filovirus Strategies to Escape Antiviral Responses

Abstract

This chapter describes the various strategies filoviruses use to escape host immune responses with a focus on innate immune and cell death pathways. Since filovirus replication can be efficiently blocked by interferon (IFN), filoviruses have evolved mechanisms to counteract both type I IFN induction and IFN response signaling pathways. Intriguingly, marburg- and ebolaviruses use different strategies to inhibit IFN signaling. This chapter also summarizes what is known about the role of IFN-stimulated genes (ISGs) in filovirus infection. These fall into three categories: those that restrict filovirus replication, those whose activation is inhibited by filoviruses, and those that have no measurable effect on viral replication. In addition to innate immunity, mammalian cells have evolved strategies to counter viral infections, including the induction of cell death and stress response pathways, and we summarize our current knowledge of how filoviruses interact with these pathways. Finally, this chapter delves into the interaction of EBOV with myeloid dendritic cells and macrophages and the associated inflammatory response, which differs dramatically between these cell types when they are infected with EBOV. In summary, we highlight the multifaceted nature of the host-viral interactions during filoviral infections.

Fig. 1

The virus family Filoviridae includes three genera, Ebolavirus, Marburgvirus, and Cuevavirus. The genus Ebolavirus has five members: Ebola virus (EBOV), Sudan virus (SUDV), Bundibugyo virus (BDBV), Tai Forest virus (TAFV), and Reston virus (RESTV). The genus Marburgvirus has two members: Marburg virus (MARV) and Ravn virus (RAVV). The genus Cuevavirus has only one member, Lloviu virus (LLOV). Viruses in red are pathogenic to humans, those in green appear to be non-pathogenic to humans, and those in blue are not known to have been in contact with humans

Fig. 2

Filoviruses inhibit the type I IFN response at multiple steps. This figure shows a simplified schematic of the type I IFN signal pathway. Viral PAMPs (e.g., dsRNA, endosomal ssRNA) are detected by host PRRs, such as RLRs (e.g., MDA5, RIG-I) and TLRs, which lead to the production of type I IFNs (IFNα/β) and pro-inflammatory cytokines. Binding of IFNα/β to the receptor complex IFNAR1/2 activates the JAK/STAT pathway leading to the expression of IFN-stimulated genes (ISGs). Filovirus proteins (in red) target different steps of these pathways