Recent advances in unveiling cellular host-Zika virus interactions in Drosophila

Current knowledge of host-Zika virus (ZIKV) interactions provides only a partial understanding of a complex and dynamic system, yielding a serious public health threat and track record that has more failures than successes. Recent work has contribu ted significantly to understand the innate immune and metabolic processes against ZIKV using the genetically tractable Drosophila host [1]. This research has provided a more comprehensive picture of sex-specific host pathology and identified novel regulators and components that govern innate defenses against ZIKV infection. Such knowledge expands our understanding of the molecular basis of viral diseases and is critical for developing anti-ZIKV therapeutic strategies as well as vector control measures.

Previous studies in mosquitoes have demonstrated the striking impact of temperature changes on ZIKV protein expression and secretion and the transcriptional response to ZIKV and other arboviruses, which in turn can substantially alter the dynamics of ZIKV replication and undermine mosquito immune responses [2–4]. Such effects may cause ZIKV reemergence and lead to major increases in persistence and transmission. To understand the dynamics of ZIKV and the impact of mitigation measures, a recent study used experimental data to parametrize a temperature-dependent model of ZIKV-induced pathogenesis and analyzed the effects of temperature variability on host fitness and innate immune responses [5]. Using the brat^chs mutants, it was demonstrated that temperature variability is a key driver of ZIKV replication, and consequently drives Drosophila mortality and motor dysfunction in a sex-dependent manner. These results implicate temperature – transmission relationships in vector-borne diseases, suggesting serious ramifications on how disease transmission changes seasonally, across geographical locations, and with future climate and land use shifts. Control tools being considered for implementation in vector management strategies may also be affected by temperature, such as conventional chemical insecticides that target a diverse range of insect pests [6]. Furthermore, it was shown that ZIKV is localized to the brat^chs brain and activates the RNAi and apoptotic immune responses. How exactly RNAi effectors regulate viral replication is thus an intriguing question, which requires the identification of putative ZIKV dsRNA targets that are recognized by Dicer-2 to provide mechanistic insight into how this pathway regulates ZIKV replication in Drosophila.

The cellular mechanisms mediating the induction of apoptosis following viral infection remain enigmatic in Drosophila, which has prevented experimental verification of the functional significance of apoptosis in limiting viral infections in insect hosts. It was recently shown, for the first time, that the Drosophila apoptotic gene Grim promotes the antiviral RNAi signaling in response to ZIKV infection in the adult brain, which attenuates viral infection. This mechanism may be effective against most types of viruses and appears to be conserved among multicellular organisms [7].

Findings from recent work also establish an in vivo model to study host metabolic processes during viral infections and highlight metabolic changes as potential comorbidities in infected flies [8]. This was the first demonstration of perturbed Drosophila carbohydrate metabolism upon ZIKV infection, which was tightly connected to host immunity. ZIKV infection results in multiple pathologies, notably the depression of metabolic rates (glucose, trehalose, and glycogen) four days post-infection as a response to physiological stress and viral replication. Whereas a moderate ZIKV load results in wild-type flies, an enhanced load in Dicer-2 mutants results in the reduced carbohydrate levels. There are many potential functional causes and consequences of these changes including: 1) infected flies are potentially increasing energy expenditure to mount a sufficient immune response; this is a host factor which could drain energy reserves, 2) ZIKV is replicating during infection, potentially consuming these resources as well. There is likely a complicated interplay between all these factors to manipulate various metabolic components and impact the survival of the host. This information provides a stepping stone from which we can launch additional and more targeted studies on metabolism to show that viral infections are a multi-faceted trade-off between host nutrition, viral replication, and investment in immunity. Studies of metabolic-immune interactions could potentiate development of more cost-effective treatments for infection by modulating our resistance and tolerance through diet shifts instead of expensive pharmaceutical drugs. Thus, they have the potential to put forward more attainable treatments and solutions to a much larger part of the global community.

In addition to unveiling humoral and cellular host-ZIKV interactions, the anti-ZIKV role of the phenoloxidase (PO)/melanization response, which forms the link between the two arms of the fly innate immune system, was recently explored [9]. Most prominent was the essential roles of prophenoloxidase genes PPO1 and PPO2 in host resistance to ZIKV infection, which greatly contributes to developing a mechanistic understanding of ZIKV pathology and immune responses such as melanization in infected flies [10]. Because of its resemblance to the mammalian clotting system, the use of Drosophila models to dissect innate immune defenses may prove useful when examining the involvement of major conserved clotting factors in mammalian immunity [11]. A homolog for the human transglutaminase clotting factor XIIIa has been identified in Drosophila. Moreover, transglutaminases have been linked to PO during the clot formation on the surface of pathogenic microbes, suggesting a role in pathogen clearance in insects [11].

Flaviviruses constitute a major threat to human health, therefore further investigations of the molecular and cellular features responsible for this underrepresented virus-host interaction may provide a promising avenue for the discovery of novel targets for medical treatments against virus-induced intractable diseases.

Funding Statement

Drosophila-Zika virus interactions work in the Eleftherianos lab is funded by the National Institute of Allergy and Infectious Diseases.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

Author contributions

Ghada Tafesh-Edwards wrote the manuscript and Ioannis Eleftherianos revised it. Both authors read and approved the final manuscript.