Treatment with mitochondrial targeting antibiotics improves survival outcomes after Flock House virus infection in young and aged Drosophila melanogaster.

Aged organisms are more susceptible to infectious diseases, including infections with RNA viruses. Mitochondrial dysfunction is one of many hallmarks of aging that could affect this increased susceptibility, as the relationship between immunity and metabolism is crucial to manage infections. Using - Flock House virus (FHV) host-virus interactions model system, previous work has identified differences in young and aged flies' ability to modulate oxygen consumption rates (OCR). Here, we hypothesized that interventions that reduce OCR could improve survival of FHV, as observed in young flies. Tetracycline (TTC) and rifampicin (RIF) antibiotics disrupt mitochondrial translation and transcription respectively because of mitochondria's bacterial ancestry. The mitochondrial unfolded protein response (UPR) is activated by mitochondrial stressors, including reactive oxygen species, defects in oxidative phosphorylation, and mitonuclear protein imbalance. UPR activation initiates retrograde signaling to the nucleus, prompting transcription, translation, and import of nuclear proteins to resolve stress. We showed TTC or RIF treatment extended survival in young and aged flies after FHV infection, independently of virus load modulation. Furthermore, we demonstrate that bacterial loads are not significantly different between FHV-infected flies and controls, and that the protective effect of TTC likely occurs independently of its antimicrobial properties. We observed increased expression of genes involved in the UPR, glycolysis, and oxidative stress response with TTC treatment. Our results suggest perturbing mitonuclear protein balance with TTC or RIF could activate the UPR and improve outcomes of virus infection.