Human & mosquito microRNA interactions with arboviruses: systematic discovery & functional roles

Mosquito-borne arboviruses (arboviruses) are major human pathogens, infecting ~400 million people each year. Many arboviruses, such as chikungunya, Zika and yellow fever, have recently globally expanded. Climate change will further increase arbovirus diseases, because warmer global temperatures will allow virus-carrying mosquitoes to spread to new areas. Thus, arboviruses are urgent public health threats, and the majority lack vaccines or specific treatments. Most pathogenic arboviruses have short RNA genomes encoding ~10 genes. This infectious RNA must infect mosquitoes to successfully infect humans. Intriguingly, while humans become sick but usually recover, mosquitoes remain infected for life, happily feeding and infecting new hosts. We still lack an understanding of how these viruses manage to cycle between these dramatically different organisms. This is particularly true in mosquitoes, where a lack of experimental and computational tools has hindered research. We will tackle this problem by using leveraging new methods we developed in mosquitoes. With these sophisticated tools, we will uncover and compare arbovirus interactions with important mosquito and human small RNAs: microRNAs (miRNAs). miRNAs regulate global cellular processes in both organisms, but the specific miRNAs and processes will be very different in each context. We know miRNAs can interact with RNA viruses to directly help or hurt the virus, or to indirectly manipulate host cells. Yet, how and why mosquito-borne viruses interact with organism-specific miRNAs is largely unexplored. This proposal will uncover miRNA interactions with arboviruses in both humans and mosquitoes. Ultimately, this research will broaden our understanding of how arbovirus infect diverse organisms and cause disease.