Molecular and Functional Characterization of Drosophila melanogaster Immunity Against Zika Virus Infection
Open AccessWith World Health Organization (WHO) scientists confirming an outbreak of Zika virus (ZIKV) in India on October 14, 2021, the characterization and understanding of the molecular mechanisms underlying immune responses against ZIKV have, once again, become ever more urgent. ZIKV is transmitted to humans primarily by the infected Aedes mosquito species, causing neurologic complications that range from sensory neuropathy and seizures to congenital Zika syndrome (microcephaly) in infants born to mothers infected during pregnancy. Nearly 700 million people contract mosquito-borne illnesses each year, causing more than one million deaths and severe public health threats in many parts of the world. These illnesses are caused commonly by members of the Flaviviridae family including Zika, Dengue, Yellow Fever, and West Nile viruses. Hence, the development of an in vivo model to uncover the complex host-ZIKV interactions and identify the molecular components involved in immune signaling are crucial to the advancement of innovative concepts and means for the efficient control of ZIKV disease and anti-flavivirus immune mechanisms in humans.Previous work presents compelling evidence that establishes the fruit fly Drosophila melanogaster as a reliable model for studying arboviruses (arthropod-borne viruses), as many of the signaling pathways identified are evolutionarily conserved amongst insect species. Particularly, the large conservation between Drosophila and mosquitoes has already paved the way for the recent, novel insights into Zika pathogenesis and host antiviral immune function using Drosophila models. Due to its rapid generation time, small size, and genetically malleable nature, Drosophila is considered a potent model that is often studied for its innate immunity, which shares significant similarities with that of vertebrate animal systems. Despite its importance in dissecting the molecular and mechanistic components of host immune responses, relatively little is known about Drosophila immunity against viral infections. The work presented here develops a fly model to study host innate immune responses to ZIKV infection. We show that temperature variability is a key driver of ZIKV pathogenesis, thereby altering host mortality and causing motor dysfunction in a sex-dependent manner. We also present evidence that ZIKV is largely localized to the fly brain and activates the RNAi and apoptotic immune responses. Furthermore, we examine ZIKV-mediated perturbed metabolism in correlation to the RNAi central mediator Dicer-2, demonstrating molecular factors that could be considered as targets to inhibit ZIKV successful replication. Lastly, we explore for the first time the contribution of the Drosophila prophenoloxidases to host survival and defenses against ZIKV infection by analyzing PPO mutations alone and in combination. Our study shows that only PPO1 and PPO2 genes contribute to host survival and appear to be upregulated following ZIKV infection in Drosophila. Findings in this work provide a foundation for developing new treatments for ZIKV infection and vector control strategies.
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