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

Summary 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 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 (FHV) due to an age-dependent defect in disease tolerance. In comparison to younger individuals, we find that older Drosophila mount larger transcriptional responses characterized by differential regulation of more genes and genes regulated to a greater extent. Our results indicate that loss of disease tolerance to FHV with age possibly results from a stronger regulation of genes involved in apoptosis, activation of the Drosophila Immune deficiency (IMD) NF-kB pathway or from downregulation of 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 sets the stage for future analysis of the age-dependent mechanisms that govern survival and control of virus infections at older age.