A Novel Mechanism Underlying the Innate Immune Response Induction upon Viral-Dependent Replication of Host Cell mRNA: A Mistake of +sRNA Viruses' Replicases

Abstract

Viruses are lifeless particles designed for setting virus-host interactome assuring a new generation of virions for dissemination. This interactome generates a pressure on host organisms evolving mechanisms to neutralize viral infection, which places the pressure back onto virus, a process known as virus-host cell co-evolution. Positive-single stranded RNA (+sRNA) viruses are an important group of viral agents illustrating this interesting phenomenon. During replication, their genomic +sRNA is employed as template for translation of viral proteins; among them the RNA-dependent RNA polymerase (RdRp) is responsible of viral genome replication originating double-strand RNA molecules (dsRNA) as intermediates, which accumulate representing a potent threat for cellular dsRNA receptors to initiate an antiviral response. A common feature shared by these viruses is their ability to rearrange cellular membranes to serve as platforms for genome replication and assembly of new virions, supporting replication efficiency increase by concentrating critical factors and protecting the viral genome from host anti-viral systems. This review summarizes current knowledge regarding cellular dsRNA receptors and describes prototype viruses developing replication niches inside rearranged membranes. However, for several viral agents it's been observed both, a complex rearrangement of cellular membranes and a strong innate immune antiviral response induction. So, we have included recent data explaining the mechanism by, even though viruses have evolved elegant hideouts, host cells are still able to develop dsRNA receptors-dependent antiviral response.

Keywords: +RNA viruses; MDA5; RIG-I; Semliki Forest Virus; TLR3; double membrane vesicle; invaginated membranes; poliovirus.

Figure 1

Proposed model of host-cell mRNA replication by +sRNA viruses' replicases. Inspired by the “Model of mutant Semiliki Forest Virus replication restriction in fibroblasts,” proposed by Nikonov et al. (2013). After viral internalization and uncoating, the genomic RNA serves as mRNA recognized by the host cell machinery to translate the viral replication complex (RdRp), which binds to the plasma membrane to build up the membranous niche called spherule. Once there, the replicase activity generates new viral genome copies producing double-stranded RNA (dsRNA) molecules as intermediates, which remain hided from the cytoplasmic sentries inside the spherules (1). Nevertheless, in the meantime, the RdRp is able to take cellular mRNA as template originating dsRNA molecules in the cytoplasm, exposed to the Pamp Recognition Receptors [PRRs (MDA-5 and RIG-I)] to initiate the innate immune response, which produces the viral restriction (2).