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

Abstract

SummaryAdvanced 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.

Loss of self-tolerance leads to altered gene expression and IMD pathway activation inDrosophila melanogaster

“…noncoding RNAs are differentially expressed in hop Tum and tuSz 1 mutants Similar to a recent study looking at the transcriptional response to aging and viral infection in Drosophila (Sheffield et al 2021), we found widespread changes in the expression of predicted noncoding RNAs (ncRNAs) in tuSz 1 and hop Tum larvae (Figure 6A-B). ncRNAs are a class of RNA molecules that are transcribed from the genome but are not translated into proteins.…”

Wolbachia endosymbionts in Drosophila regulate the resistance to Zika virus infection in a sex dependent manner

“…Further efforts will focus on testing whether the observed effects are specific to the D. melanogaster line Canton-S and the Wolbachia pipientis strain wMel, and also to other Drosophila species. Considering that recent research has indicated that antiviral immunity in the fly is age dependent (Sheffield et al, 2021), it is intriguing to investigate the influence of age on the Wolbachia protective effect against Zika virus infection in female flies. Because hemocytes, autophagy, and the prophenoloxidase system contribute to D. melanogaster antiviral immunity (Lamiable et al, 2016;, potential input of Wolbachia to these aspects of the immune response against Zika virus will also be examined.…”

The Impact of Age on Response to Infection in Drosophila

“…Disease tolerance at older age may be very important for antiviral defense in Drosophila . In a recent study, Sheffield and colleagues found that, despite displaying an increased susceptibility to FHV infection, older (30 day-old) wild-type ( OregonR ) flies do not accumulate higher virus titers than their younger (5 day-old) counterparts [ 106 ]. Intriguingly, a similar pattern has been observed in humans following infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pathogen responsible for COVID-19.…”