Ageing leads to reduced specificity of antimicrobial peptide responses in Drosophila melanogaster

Abstract

Evolutionary theory predicts a late-life decline in the force of natural selection, possibly leading to late-life deregulations of the immune system. A potential outcome of such deregulations is the inability to produce specific immunity against target pathogens. We tested this possibility by infecting multiple Drosophila melanogaster lines (with bacterial pathogens) across age groups, where either individual or different combinations of Imd- and Toll-inducible antimicrobial peptides (AMPs) were deleted using CRISPR gene editing. We show a high degree of non-redundancy and pathogen-specificity of AMPs in young flies: in some cases, even a single AMP could confer complete resistance. However, ageing led to drastic reductions in such specificity to target pathogens, warranting the action of multiple AMPs across Imd and Toll pathways. Moreover, use of diverse AMPs either lacked survival benefits or even accompanied survival costs post-infection. These features were also sexually dimorphic: females required a larger repertoire of AMPs than males but extracted equivalent survival benefits. Finally, age-specific expansion of the AMP-repertoire was accompanied with ageing-induced downregulation of negative-regulators of the Imd pathway and damage to renal function post-infection, as features of poorly regulated immunity. Overall, we could highlight the potentially non-adaptive role of ageing in producing less-specific AMP responses, across sexes and pathogens.

Unraveling the Role of Antimicrobial Peptides in Insects

“…Recently, using Drosophila lines with different combinations of knocked out AMP genes, the pathogen-specific roles of AMPs have been reported, where microbicidal activity against a particular pathogen depended mainly on a certain AMP, e.g., the Dpt gene family alone provided effective defense against Providencia rettgeri , drosocin contributed to defense against Enterobacter cloacae , whereas buletin (also encoded by the Dro gene) was effective against Providencia burhodogranariea [ 63 , 64 ]. In addition to these findings, it turned out that when considering the role of AMPs in Drosophila response to infection, age and sexual dimorphism should be taken into account given the documented strong differences in immune response at the basal level upon infection and during aging between sexes [ 65 , 66 ]. Hanson et al showed that Dpt expression was sufficient to protect young male flies against P. rettgeri ; however, Shit et al demonstrated that reintroduction of functional Dpt A and Dpt B (∆ AMPs +Dpt ) fully restored survival and decreased the P. rettgeri load only in young males but not in females or older males [ 63 , 66 ].…”

“…In addition to these findings, it turned out that when considering the role of AMPs in Drosophila response to infection, age and sexual dimorphism should be taken into account given the documented strong differences in immune response at the basal level upon infection and during aging between sexes [ 65 , 66 ]. Hanson et al showed that Dpt expression was sufficient to protect young male flies against P. rettgeri ; however, Shit et al demonstrated that reintroduction of functional Dpt A and Dpt B (∆ AMPs +Dpt ) fully restored survival and decreased the P. rettgeri load only in young males but not in females or older males [ 63 , 66 ]. Aging had negative effects on the fitness and pathogen clearance ability of Drosophila females but not males.…”

“…Most mutant flies lacking a certain AMP, or a combination of AMPs, became highly susceptible to infection with age, with the exception of female mutants lacking Def. This effect may be related to the sexual dimorphism, where defensin is important for defense in males but not in females [ 66 ].…”

Mosquito ageing modulates the development, virulence and transmission potential of pathogens

“…Yet, the widespread occurrence of immunosenescence across the tree of life, including in insects [14], suggests the opposite—that is, a decline in immune function, and hence in parasite resistance with age [15,16]. In insects, studies have revealed that immunosenescence can manifest as excessive, overly reactive and less specific immune responses, without any notable improvement in survival [17–19]. Furthermore, different components of the insect immune response (enzymatic versus cellular) can display distinct age-specific patterns [16].…”

Mosquito aging modulates the development, virulence and transmission potential of pathogens

“…Yet, the widespread occurrence of immunosenescence across the tree of life, including in insects [14], suggests the opposite; that is, a decline in immune function, and hence in parasite resistance with age [15,16]. In insects, studies have revealed that immunosenescence can manifest as excessive, overly-reactive and less specific immune responses, without any notable improvement in survival [17][18][19]. Furthermore, different components of the insect immune response (enzymatic versus cellular) can display distinct agespecific patterns [16].…”