Interaction of the innate immune system with positive-strand RNA virus replication organelles

Abstract

The potential health risks associated with (re-)emerging positive-strand RNA (+RNA) viruses emphasizes the need for understanding host-pathogen interactions for these viruses. The innate immune system forms the first line of defense against pathogenic organisms like these and is responsible for detecting pathogen-associated molecular patterns (PAMPs). Viral RNA is a potent inducer of antiviral innate immune signaling, provoking an antiviral state by directing expression of interferons (IFNs) and pro-inflammatory cytokines. However, +RNA viruses developed various methods to avoid detection and downstream signaling, including isolation of viral RNA replication in membranous viral replication organelles (ROs). These structures therefore play a central role in infection, and consequently, loss of RO integrity might simultaneously result in impaired viral replication and enhanced antiviral signaling. This review summarizes the first indications that the innate immune system indeed has tools to disrupt viral ROs and other non- or aberrant-self membrane structures, and may do this by marking these membranes with proteins such as microtubule-associated protein 1A/1B-light chain 3 (LC3) and ubiquitin, resulting in the recruitment of IFN-inducible GTPases. Further studies should evaluate whether this process forms a general effector mechanism in +RNA virus infection, thereby creating the opportunity for development of novel antiviral therapies.

Keywords: +RNA virus; GTPases; Interferon; Replication organelles.

Fig. 1

Viral replication organelles. (A) Schematic representation of viral replication organelles (ROs), modified from . Membranous structures that form ROs can be categorized as the invaginated vesicle/spherule (Inv) type (left), and the double membrane vesicle (DMV) type (right). Inv ROs are predominantly observed during infection with alphaviruses, such as Semliki Forest virus (SFV), nodavirideae such as flock house virus (FHV), and flaviviridae such as rubella virus (RUBV), dengue virus (DENV), and West Nile virus (WNV). Alternatively, double membrane vesicle (DMV) type ROs are formed by enteroviruses coxsackievirus B3 (CVB3) and poliovirus (PV), coronaviruses severe acute respiratory coronavirus (SARS-CoV) and equine arteritis virus (EAV), and the flavivirus hepatitis C virus (HCV). (B) 3D reconstruction of Inv ROs upon DENV infection, modified from (C) 3D reconstruction of DMV ROs upon HCV infection modified from .

Fig. 2

LC3 recruits IFN-γ inducible GTPases to disrupt the parasitophorus vacuole of Toxoplasma gondii. Upon invasion of the host cell, Toxoplasma gondii (T. gondii) resides in a host-derived membranous structure, termed the parasitophorus vacuole membrane (PVM), to evade immune detection. Recent studies demonstrate that LC3 is conjugated to the PVM by the LC3 conjugation system, leading to recruitment of IFN-γ inducible GTPases to the PVM upon IFN-γ stimulation. As a consequence, activation of IFN-γ inducible GTPases leads to membrane disruption of the PVM, and exposure of T. gondii to the innate immune system.

Fig. 3

A possible role for IFN-inducible GTPases in the targeting of viral replication organelles. Upon infection, +RNA viruses hamper IFN and ISG induction at multiple levels to decelerate innate immune detection. Viral replication organelles (ROs) are believed to have a dual role in +RNA virus infection and innate immune evasion, as they facilitate efficient RNA replication while shielding viral RNA from the host. Based on current knowledge, we hypothesize the existence of host cell IFN-inducible GTPases aimed to disrupt ROs, thereby exposing viral RNA and promoting antiviral signaling. IFNR: interferon receptor.