Metabolic homeostasis favors tolerance to persistent viral infection in Aedes aegypti mosquitoes

The mosquito Aedes aegypti harbors a wide range of persistent viral infections, including both medically important arboviruses and insect-specific viruses (ISVs). However, the mechanisms underpinning establishment and maintenance of persistent viral infections remain poorly understood despite them influencing viral dynamics and transmission. Differently than arboviruses, which circulate at lower frequencies, ISVs are highly prevalent in field mosquitoes, thus representing ideal models to study the mechanisms of persistence. On this basis, we followed infection of the ISV cell-fusing agent virus (CFAV) in two Ae. aegypti laboratory populations, Liverpool (LVP) and ZacPanda (ZacP), and studied their immune responses, including resistance and tolerance, along with physiological and fitness impacts of CFAV infection. Our results demonstrate that CFAV establishes life-long infections with a comparable activation of resistance mechanisms, in both LVP and ZacP mosquitoes. In contrast, ZacP mosquitoes exhibited greater tolerance to CFAV than LVP accompanied by the ability to maintain metabolic homeostasis during infection. In neither ZacP nor LVP, CFAV resulted in reproductive impairment. These findings highlight a key role for tolerance mechanisms, which through regulation of energetic resources, contribute to sustain persistent viral infections in mosquitoes. Our results have implications for viral transmission dynamics and vector control strategies.