Emerging Mechanisms of Insulin-Mediated Antiviral Immunity in Drosophila melanogaster

Abstract

Arboviruses (arthropod-borne viruses), such as Zika (ZIKV), West Nile (WNV), and dengue (DENV) virus, include some of the most significant global health risks to human populations. The steady increase in the number of cases is of great concern due to the debilitating diseases associated with each viral infection. Because these viruses all depend on the mosquito as a vector for disease transmission, current research has focused on identifying immune mechanisms used by insects to effectively harbor these viruses and cause disease in humans and other animals. Drosophila melanogaster are a vital model to study arboviral infections and host responses as they are a genetically malleable model organism for experimentation that can complement analysis in the virus' natural vectors. D. melanogaster encode a number of distinct mechanisms of antiviral defense that are found in both mosquito and vertebrate animal systems, providing a viable model for study. These pathways include canonical antiviral modules such as RNA interference (RNAi), JAK/STAT signaling, and the induction of STING-mediated immune responses like autophagy. Insulin signaling plays a significant role in host-pathogen interactions. The exact mechanisms of insulin-mediated immune responses vary with each virus type, but nevertheless ultimately demonstrates that metabolic and immune signaling are coupled for antiviral immunity in an arthropod model. This mini review provides our current understanding of antiviral mechanisms in D. melanogaster, with a focus on insulin-mediated antiviral signaling, and how such immune responses pertain to disease models in vertebrate and mosquito species.

Keywords: JAK/STAT; RNA interference; STING; West Nile virus; Zika virus; dengue virus; innate immunity; insulin.

Figure 1

Drosophila melanogaster are an ideal model organism for studying host-arboviral interactions. Various arboviruses utilize mosquitoes as reservoirs and vectors for transmission into vertebrate hosts. This can include species that are either involved in viral replication and spread (such as bird populations for West Nile virus) or dead-end host that become infected without being able to properly propagate viral replication for further spread (i.e., humans). Transmission is accomplished via a bloodmeal exchange. Drosophila possess orthologous host response pathways found in mosquitoes and humans, making it an ideal model organism for studying transmission dynamics and host-pathogen interactions at both vector and human level.

Figure 2

Innate immune antimicrobial pathways are conserved in arthropods. Insects utilize RNAi (A), STING-mediated immunity (B), and JAK/STAT signaling (D) in order to effectively respond to various arboviruses at different stages of infection. The IIS pathway (C) is an important mediator in host immunity as it regulates which immune responses are active or suppressed. During times of starvation, RNAi is more active while the bloodmeal provides the needed insulin to suppress RNAi and activate JAK/STAT. STING-mediated immunity has not yet been directly linked to IIS but may be affected by broader nutritional signaling. Each of these pathways, to varying degrees, are conserved in fly, mosquito, and human systems with different efficiencies in responding to viral infection.