Drosophila melanogaster Limostatin and Its Human Ortholog Promote West Nile Virus Infection

Insect-borne viruses, such as those of the Flaviviridae family, pose a serious risk to global health. WNV, a mosquito-borne flavivirus, is transmitted primarily by the Culex mosquito. Despite the increasing exposure of populations to mosquito-borne flaviviruses and the expanding range of the vector mosquito, there are limited resources available to prevent or treat flavivirus infections. Using the model organism Drosophila melanogaster, commonly known as the fruit fly, we previously found that insulin signaling reduces WNV infection. We translated these finding to mosquitoes and human cells and showed similar mechanisms of insulin-mediated antiviral activity. However, insect and mammalian hormones can regulate insulin signaling. Specifically, decretin hormones suppress insulin secretion, especially during periods of starvation and low glucose intake. In this study, we show that the insect decretin, Limostatin, and its mammalian ortholog, Neuromedin U, can promote WNV infection. These results suggest that the inhibition of decretin signaling may be a novel therapeutic target to control WNV infection. The arbovirus West Nile virus (WNV) is a danger to global health. Spread primarily by mosquitoes, WNV causes about 2000 cases per year in the United States. The natural mosquito immune response controls viral replication so that the host survives but can still transmit the virus. Using the genetically malleable Drosophila melanogaster model, we previously dissected innate immune pathways used to control WNV infection. Specifically, we showed that insulin/IGF-1 signaling (IIS) activates a JAK/STAT-mediated immune response that reduces WNV. However, how factors that regulate IIS in insects control infection has not been identified. D. melanogaster Limostatin (Lst) encodes a peptide hormone that suppresses insulin secretion. Its mammalian ortholog, Neuromedin U (NMU), is a peptide that regulates the production and secretion of insulin from pancreatic beta cells. In this study, we used D. melanogaster and human cell culture models to investigate the roles of these insulin regulators in immune signaling. We found that D. melanogaster Lst mutants, which have elevated insulin-like peptide expression, are less susceptible to WNV infection. Increased levels of insulin-like peptides in these flies result in upregulated JAK/STAT activity, leading to protection from infection. Treatment of human cells with the insulin regulator NMU results in increased WNV replication. Further investigation of methods to target Lst in mosquitoes or NMU in mammals can improve vector control methods and may lead to improved therapeutics for human and animal infection.