RNA virus-mediated changes in organismal oxygen consumption rate in young and old Drosophila melanogaster males.

Aging is accompanied by increased susceptibility to infections including with viral pathogens resulting in higher morbidity and mortality among the elderly. Significant changes in host metabolism can take place following virus infection. Efficient immune responses are energetically costly, and viruses divert host molecular resources to promote their own replication. Virus-induced metabolic reprogramming could impact infection outcomes, however, how this is affected by aging and impacts organismal survival remains poorly understood. RNA virus infection of Drosophila melanogaster with Flock House virus (FHV) is an effective model to study antiviral responses with age, where older flies die faster than younger flies due to impaired disease tolerance. Using this aged host-virus model, we conducted longitudinal, single-fly respirometry studies to determine if metabolism impacts infection outcomes. Analysis using linear mixed models on Oxygen Consumption Rate (OCR) following the first 72-hours post-infection showed that FHV modulates respiration, but age has no significant effect on OCR. However, the longitudinal assessment revealed that OCR in young flies progressively and significantly decreases, while OCR in aged flies remains constant throughout the three days of the experiment. Furthermore, we found that the OCR signature at 24-hours varied in response to both experimental treatment and survival status. FHV-injected flies that died prior to 48- or 72-hours measurements had a lower OCR compared to survivors at 48-hours. Our findings suggest the host's metabolic profile could influence the outcome of viral infections.

Age-dependent impairment of disease tolerance is associated with a robust transcriptional response following RNA virus infection in Drosophila.

Advanced age in humans is associated with greater susceptibility to and higher mortality rates from infections, including infections with some RNA viruses. The underlying innate immune mechanisms, which represent the first line of defense against pathogens, remain incompletely understood. Drosophila melanogaster is able to mount potent and evolutionarily conserved innate immune defenses against a variety of microorganisms including viruses and serves as an excellent model organism for studying host-pathogen interactions. With its relatively short lifespan, Drosophila also is an organism of choice for aging studies. Despite numerous advantages that this model offers, Drosophila has not been used to its full potential to investigate the response of the aged host to viral infection. Here, we show that, in comparison to younger flies, aged Drosophila succumb more rapidly to infection with the RNA-containing Flock House virus due to an age-dependent defect in disease tolerance. Relative to younger individuals, we find that older Drosophila mount transcriptional responses characterized by differential regulation of more genes and genes regulated to a greater extent. We show that loss of disease tolerance to Flock House virus with age associates with a stronger regulation of genes involved in apoptosis, some genes of the Drosophila immune deficiency NF-kB pathway, and genes whose products function in mitochondria and mitochondrial respiration. Our work shows that Drosophila can serve as a model to investigate host-virus interactions during aging and furthermore sets the stage for future analysis of the age-dependent mechanisms that govern survival and control of virus infections at older age.