Comptes Rendus

The insect reservoir of diversity for viruses and antiviral mechanisms
Comptes Rendus. Biologies, Volume 342 (2019) no. 7-8, pp. 260-262.


Insects originated more than 400 million years ago and have undergone since then an extraordinary diversification, associated with many spectacular innovations, such as flying or establishment of social societies. They have colonized all terrestrial ecosystems, and are exposed to a broad range of pathogens, including viruses, bacteria, fungi, and parasites. Like all animals, insects rely on innate immunity to control infections. Innate immunity is the first layer in host-defense in animals. It involves receptors sensing the presence of infectious microorganisms and triggering signaling that leads to the expression of genes coding effector molecules, which concur to counter the infection. In vertebrates, a subset of genes induced encode cytokines and coreceptors that activate a second layer of host defense known as adaptive immunity. The study of the innate immunity in insects has led to (i) the discovery of antimicrobial peptides, which target bacteria and fungi and are now known to be present in all animals and in plants, (ii) the identification of evolutionarily conserved important genes activating innate immunity, e.g., the Toll-like receptors, and (iii) a better understanding of viral and parasitic diseases transmitted by hematophagous vector insects.

Among infectious microbes, viruses represent a particular threat because they offer few intrinsic targets for inhibition by antiviral molecules. This is because they consist in their simplest form in a nucleic acid encapsulated in a protein shell, and hijack molecular machineries from host cells to complete their replication cycle. Of note, recent advances in high-throughput sequencing (HTS) technologies have opened the way to the characterization of the virome (i.e. the genetic diversity of viruses in a biological sample) in insects. Interestingly, these studies revealed that (i) infection by one or more viruses is common in arthropods, (ii) the genetic diversity of arthropod viruses surpasses that described previously, and (iii) the genetic diversity of viruses found in plants and vertebrate animals fall within the genetic diversity of viruses associated with arthropods [1].

This suggests that arthropods may have participated in the evolution of viruses causing human disease and points to the relevance of characterizing antiviral mechanisms in insects.

One reason to investigate insect–virus interactions is that hematophagous insects, for example Aedes mosquitoes, are vectors of important viral diseases such as Zika, dengue, yellow fever, and chikungunya. RNA interference is an RNA-based mechanism that offers broad protection against viruses in insects. This elegant mechanism relies on the recognition of double + stranded (ds) viral RNAs by the RNase III enzyme Dicer-2, which processes them into 21 nucleotide long small interfering (si) RNA duplexes. One strand of the siRNA is then loaded onto the RNAse H-like enzyme Argonaute 2, where it serves as a guide to specifically target viral RNAs. Of note, virus-derived siRNAs, which provide a footprint of the action of the insect immune system, can be characterized by HTS. In collaboration with the group of Prof. Joao Marques (UFMG, Belo Horizonte, Brazil), we have shown that small RNA sequencing allows assembling longer contigs of viral RNAs, generating a better coverage of viral genomes, than traditional long RNA sequencing. In addition, the profile of the small RNAs is characteristic of the virus from which they derive (e.g., number of reads, size distribution of the small RNAs). For example, some viruses infect the ovaries and generate a different type of small RNAs, known as Piwi-interacting RNAs, or piRNAs, which are longer (24–28nt) than siRNAs (Fig. 1). As a result, it is possible to assign a viral origin to sequences even if they do not exhibit any homology to sequences present in the databases. This represents a significant improvement in the characterization of the insect virome [2]. We have applied this strategy to wild Aedes mosquitoes collected in a dengue endemic region in Brazil, and have identified three viruses. Two of them, the Bunyavirus Phasi Charoen-like virus (PCLV) and the unclassified virus Humaita-Tubiacanga virus (HTV), have a high prevalence in Aedes mosquitoes collected in different regions of Brazil. These poorly characterized viruses may affect the dynamics of transmission of known viral pathogens such as dengue, Zika, or chikungunya viruses, a hypothesis that is currently being tested in the laboratory.

The discovery of the important role played by Toll-like receptors in innate immunity revealed that important gene regulatory networks have been conserved during evolution and illustrated how studies in insects can lead to important findings for the biomedical field. This has provided strong incentives to identify and characterize other evolutionarily conserved host-defense mechanisms. As a consequence, the contribution of non-conserved genes to insect immunity has received less attention. Yet, these genes may be just as important as the conserved genes. Indeed, insects evolved independently of mammals for several hundreds of thousands of years, which provided multiple opportunities to develop original strategies of defense against infections. Hence, the characterization of insect-specific antiviral factors may inspire new strategies to counter infections. For example, we recently characterized the gene diedel, which is strongly induced following viral infection in Drosophila, and has been hijacked at least three times by insect DNA viruses. We showed that diedel encodes a circulating protein that suppresses the activity of the immune deficiency (IMD) pathway of host-defense. The IMD pathway is one of the two major innate immunity pathways regulating transcription factors of the NF-κB family in flies. The discovery that several insect viruses have hijacked a cellular gene suppressing the IMD pathway prompted us to investigate its contribution to the control of viral infections. Interestingly, we discovered that two components of the pathway, the kinase IKKβ and the NF-κB transcription factor Relish, are required to restrict infection by two picorna-like viruses, Drosophila C Virus (DCV) and Cricket Paralysis Virus (CrPV) in Drosophila. By contrast, the other components of the pathway, including the regulatory subunit of the IKKβ kinase, NEMO, do not appear to play a role in the resistance to infection by these viruses. Among the genes regulated by IKKβ in virus-infected flies, we identified two genes involved in the resistance to viral infection. The first one is the homologue of the mammalian factor STING (Stimulator of Interferon Genes), and we could show that it acts upstream of IKKβ and Relish in a new signaling pathway (Fig. 2). The second one encodes a new antiviral factor, that we called Nazo (meaning “enigma” in Japanese) [3]. The STING-IKKβ-Relish signaling cassette controls inducible expression of Nazo in response to viral infection. Nazo results from a duplication of the gene CG3740 in Drosophila species from the Sophophora subgenus. Of note, CG3740 is not upregulated by viral infection, and ectopic expression of the gene has no effect on replication of DCV or CrPV, unlike expression of Nazo, which results in strong suppression of viral replication. The discovery of Nazo provides an excellent opportunity to decipher the genetics by which a cellular gene acquires a new function in antiviral immunity. Furthermore, the characterization of its mode of action against picorna-like viruses may reveal novel angles of attack against a family of viruses that include many serious human pathogens (e.g., poliovirus).

In summary, the fantastic diversity of insects extends to the viruses they carry, and to the genetic mechanisms they evolved to control these viruses. This biodiversity provides a unique opportunity to extend the repertoire of known antiviral mechanisms and to identify weak spots in the replication cycles of viruses.

Published online:
DOI: 10.1016/j.crvi.2019.09.015

Jean-Luc Imler 1

1 Unité “Modèles insectes d’immunité innée” (M3i), Institut de biologie moléculaire et cellulaire du CNRS, Université de Strasbourg, France
     author = {Jean-Luc Imler},
     title = {The insect reservoir of diversity for viruses and antiviral mechanisms},
     journal = {Comptes Rendus. Biologies},
     pages = {260--262},
     publisher = {Elsevier},
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     number = {7-8},
     year = {2019},
     doi = {10.1016/j.crvi.2019.09.015},
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Jean-Luc Imler. The insect reservoir of diversity for viruses and antiviral mechanisms. Comptes Rendus. Biologies, Volume 342 (2019) no. 7-8, pp. 260-262. doi : 10.1016/j.crvi.2019.09.015. https://comptes-rendus.academie-sciences.fr/biologies/articles/10.1016/j.crvi.2019.09.015/

Version originale du texte intégral

Disclosure of interest

The author declares that he has no competing interest.


[1] M. Shi et al. Redefining the invertebrate RNA virosphere, Nature, Volume 540 (2016), pp. 539-543

[2] E.R. Aguiar et al. Sequence-independent characterization of viruses based on the pattern of viral small RNAs produced by the host, Nucl. Acids Res., Volume 43 (2015), pp. 6191-6206

[3] A. Goto et al. The kinase IKKβ regulates a STING- and NF-κB- dependent antiviral response pathway in Drosophila, Immunity, Volume 49 (2018), pp. 225-234

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