Arboviruses and the Challenge to Establish Systemic and Persistent Infections in Competent Mosquito Vectors: The Interaction With the RNAi Mechanism

Abstract

Arboviruses are capable to establish long-term persistent infections in mosquitoes that do not affect significantly the physiology of the insect vectors. Arbovirus infections are controlled by the RNAi machinery via the production of viral siRNAs and the formation of RISC complexes targeting viral genomes and mRNAs. Engineered arboviruses that contain cellular gene sequences can therefore be transformed to “viral silencing vectors” for studies of gene function in reverse genetics approaches. More specifically, “ideal” viral silencing vectors must be competent to induce robust RNAi effects while other interactions with the host immune system should be kept at a minimum to reduce non-specific effects. Because of their inconspicuous nature, arboviruses may approach the “ideal” viral silencing vectors in insects and it is therefore worthwhile to study the mechanisms by which the interactions with the RNAi machinery occur. In this review, an analysis is presented of the antiviral RNAi response in mosquito vectors with respect to the major types of arboviruses (alphaviruses, flaviviruses, bunyaviruses, and others). With respect to antiviral defense, the exo-RNAi pathway constitutes the major mechanism while the contribution of both miRNAs and viral piRNAs remains a contentious issue. However, additional mechanisms exist in mosquitoes that are capable to enhance or restrict the efficiency of viral silencing vectors such as the amplification of RNAi effects by DNA forms, the existence of incorporated viral elements in the genome and the induction of a non-specific systemic response by Dicer-2. Of significance is the observation that no major “viral suppressors of RNAi” (VSRs) seem to be encoded by arboviral genomes, indicating that relatively tight control of the activity of the RNA-dependent RNA polymerase (RdRp) may be sufficient to maintain the persistent character of arbovirus infections. Major strategies for improvement of viral silencing vectors therefore are proposed to involve engineering of VSRs and modifying of the properties of the RdRp. Because of safety issues (pathogen status), however, arbovirus-based silencing vectors are not well suited for practical applications, such as RNAi-based mosquito control. In that case, related mosquito-specific viruses that also establish persistent infections and may cause similar RNAi responses may represent a valuable alternative solution.

Vector Specificity of Arbovirus Transmission

“…More precisely, the production of vDNA, which has been detected in mosquitoes or in Drosophila after challenge with CHIKV or Flock House virus (FHV), respectively, promotes the viral tolerance ( Goic et al, 2013 ). This process has been likely linked to RNAi pathways, considered as the most important immune pathways in arthropod vectors ( Liu et al, 2019 ). One class of interfering RNA (PIWI)-interacting RNAs, are involved in regulating insertion of TEs ( Arensburger et al, 2011 ; Akbari et al, 2013 ) and in mosquito antiviral defenses (see next section) ( Morazzani et al, 2012 ; Vodovar et al, 2012 ).…”

Comparison of Chikungunya Virus and Zika Virus Replication and Transmission Dynamics in Aedes aegypti Mosquitoes

“…Arboviruses persistently infect mosquitoes throughout their life span of approximately 2-4 weeks in nature, 7 but it is unknown whether virus titers remain consistent in all tissues over time. When competent mosquito vectors take a blood meal containing virus, the virus first replicates in the midgut, then disseminates through the mosquito body, and finally reaches the salivary glands, where it may be transmitted with saliva during a subsequent blood meal.…”

Understanding the Mechanisms Underlying Host Restriction of Insect-Specific Viruses

“…In recent years, there has been an increasing interest in the antiviral immune response of mosquitoes against dual-host arboviruses [50][51][52][53]. Different experimental studies were performed to investigate the delicate balance between mosquito immune response and the persistent viral infection mediated by arboviruses.…”