Mosquito Defense Strategies against Viral Infection

Abstract

Mosquito-borne viral diseases are a major concern of global health and result in significant economic losses in many countries. As natural vectors, mosquitoes are very permissive to and allow systemic and persistent arbovirus infection. Intriguingly, persistent viral propagation in mosquito tissues neither results in dramatic pathological sequelae nor impairs the vectorial behavior or lifespan, indicating that mosquitoes have evolved mechanisms to tolerate persistent infection and developed efficient antiviral strategies to restrict viral replication to nonpathogenic levels. Here we provide an overview of recent progress in understanding mosquito antiviral immunity and advances in the strategies by which mosquitoes control viral infection in specific tissues.

Keywords: antiviral immunity; arbovirus; mosquito.

Figure 1. Key Figure. Schematic overview of mosquito antiviral mechanisms

Mosquitoes ingest an arboviral-infected blood meal into the midgut. After replication in the midgut epithelial cells, the virus escapes into the hemolymph and subsequently spreads via the hemolymph circulation to the fat body, muscles, salivary glands and neural tissue. Mosquitoes have evolved systemic (A) and tissue-specific (B–E) antiviral mechanisms to limit viral propagation to a tolerable level. (A) The insect Toll and Imd pathways (left) are closely related to the mammalian Toll-like receptor (TLR) and tumor necrosis factor (TNF) pathways. The viral pattern recognition receptors in the Toll and Imd pathways are unknown. The Toll pathway uses viral pattern recognition to initiate an extracellular signaling cascade for the maturation of Spatzle (Spz), which is a ligand that binds the Toll receptor. The intracellular signaling pathway is mediated by Myd88 and results in the translocation of the NF-kB-like factor Rel1 to the nucleus to initiate downstream transcription. In the Imd pathway, there is an unknown pattern recognition receptor that binds viruses to recruit the adaptor molecules Imd and FADD, which results in activation of an NF-kB-like factor Rel2. The activated Rel2 translocates to the nucleus to induce the transcription of immune genes such as multiple AMPs. The functional information of the siRNA pathway (center) was obtained from Drosophila studies. Briefly, viral siRNAs are generated by double-stranded RNA (dsRNA) either as viral replication intermediates or as a part of RNA viral genomes. Dicer-2 (Dcr2) acts as the pattern recognition receptor to recognize the dsRNA. R2D2 is a protein containing two dsRNA-binding domains (R2) and is associated with Dcr2 (D2), which is required to initiate the subsequent antiviral defense. The long dsRNA is processed into siRNAs that are approximately 21–23 bp in length. The siRNAs are then incorporated into the RNA-induced silencing complex (RISC) to specifically recognize viral sequences and degrade viral mRNAs and genomes. The activation of the Drosophila JAK-STAT pathway (right) is initiated by the recognition of the extracellular unpaired ligand Upd by the transmembrane receptor Domeless (Dome). Dome is an ortholog of the mammalian type I cytokine receptor. The ligand-receptor interaction undergoes a conformational change that causes the auto-phosphorylation of Hop, which is a homologue of the mammalian JAK kinase. Activated Hop subsequently phosphorylate Dome, leading to the phosphorylation and dimerization of STAT. The activated STAT dimer translocates into the nucleus and activates the transcription of specific target genes. Orthologs of the core JAK-STAT pathway components have been identified in mosquitoes. In addition to their systemic antiviral mechanisms, mosquitoes also contain the following specific antiviral responses in various tissues: RNAi/Toll/JAK-STAT pathways and microbiota in the midgut (B), the PO system and complement-like cascade in the hemolymph/hemocytes (C), and multiple antiviral effectors in the salivary glands (D) and neural system (E). Broken arrows represent secreted processes, and unbroken arrows represent signaling processes. Abbreviations: AaHig, A. aegypti Hikaru genki; AaMCR, A. aegypti macroglobulin complement-related factor; AaSR-C, A. aegypti scavenger receptor-C; AMP, antimicrobial peptide; AnkP, ankyrin repeat-containing protein; CEC, cecropin; Cyst, cystatin; dsRNA, double-stranded RNA; Dcr-2, Dicer-2; FADD, Fas-associated death domain containing protein; Imd, Immune deficiency factor; Myd88, myeloid differentiation primary response gene 88; NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells; PO, phenoloxidase; PRR, pattern recognition receptor; RISC, RNA-induced silencing complex; RNAi, RNA interference; R2D2, a protein containing two dsRNA-binding domains (R2) and associated with Dcr2 (D2); Spz , Spatzle; STAT, signal transduction and activators of transcription; viRNA, virus-induced RNA; Vir-1, virus-induced RNA-1.