inTOLERABLE

Mosquitoes show a remarkable ability to sustain persistent viral infections without obvious signs of disease. Known as disease tolerance, this property is critical to the transmission of major human pathogens, such as dengue, Zika and yellow fever viruses. We previously discovered that upon RNA virus infection of Drosophila melanogaster, fly survival requires the synthesis of viral DNA species by retrotransposon-encoded reverse transcriptases (RTs), which boost antiviral defenses. Interestingly, treating Aedes mosquitoes with RT inhibitors also resulted in the death of infected insects, leading us to hypothesize that retrotransposon-virus interactions enable mosquitoes to tolerate infection and transmit viruses. However, the identity and function of the retrotransposons involved, and the relevance to viral tolerance in natural mosquito populations remain unknown. We propose to investigate this hypothesis through a synergistic alliance integrating antiviral immunity (Saleh lab), retrotransposon biology (Cristofari lab), and mosquito biology (Lambrechts lab). Our goal is to render viral infections inTOLERABLE for mosquitoes by identifying and genetically inactivating the source(s) of RT activity responsible for viral DNA synthesis and tolerance. This goal will be achieved using a tailored sequencing and gene editing approach designed to overcome technical challenges associated with the repetitive and dispersed nature of retrotransposons in the mosquito genome. This strategy will be applied not only to reference mosquito strains but also to a panel of field-derived populations of the major vectors Aedes aegypti and Aedes albopictus. Elucidating how retrotransposons shape the equilibrium between mosquitoes and viruses will establish a new conceptual framework by which to understand mosquito tolerance of pathogenic viruses and will lay the foundation of a novel disease prevention strategy based on the selective elimination of infected vectors.