A single amino acid polymorphism in natural Metchnikowin alleles ofDrosophilaresults in systemic immunity and life history tradeoffs

Abstract

Antimicrobial peptides (AMPs) are at the interface of interactions between hosts and microbes and are therefore expected to be fast evolving in a coevolutionary arms race with pathogens. In contrast, previous work demonstrated that one AMP, Metchikowin (Mtk), has a single residue that segregates as either proline (P) or arginine (R) in populations of four differentDrosophilaspecies, some of which diverged more than 10 million years ago. The recurrent finding of this polymorphism regardless of geography or host species, coupled with evidence of balancing selection inDrosophilaAMPs, suggest there is a distinct functional importance to each allele. The most likely hypotheses involve alleles having specificity to different pathogens or the more potent allele conferring a cost on the host. To assess their functional differences, we createdD. melanogasterlines with the P allele, R allele, or Mtk null mutation using CRISPR/Cas9 genome editing. Here, we report results from experiments assessing the two hypotheses using these lines. In males, testing of systemic immune responses to a repertoire of bacteria and fungi demonstrated that the R allele performs as well or better than the P and null alleles with most infections. With some pathogens, however, females show results in contrast with males where Mtk alleles either do not contribute to survival or where the P allele outperforms the R allele. In addition, measurements of life history traits demonstrate that the R allele is more costly in the absence of infection for both sexes. These results provide strongin vivoevidence that differential fitness with or without infection and sex-based functional differences in alleles may be adaptive mechanisms of maintaining immune gene polymorphisms in contrast with expectations of rapid evolution. Therefore, a complex interplay of forces including pathogen species and host sex may lead to balancing selection for immune genotypes. Strikingly, this selection may act on even a single amino acid polymorphism in an AMP.

Ecology-relevant bacteria drive the evolution of host antimicrobial peptides in Drosophila

“…In Drosophila, AMP genes are transcriptionally regulated by the Toll and Imd nuclear factor-kB (NF-kB) signaling pathways (8). Recent work has shown that individual effectors can play prominent roles in the defense against specific pathogens (11)(12)(13)(14)(15)(16)(17)(18)(19). Consistent with this, population genetics studies have highlighted genetic variants in AMPs correlated with susceptibility against specific pathogens.…”

Antimicrobial peptides do not directly contribute to aging in Drosophila, but improve lifespan by preventing dysbiosis

“… Badinloo et al (2018) found that chronic and ubiquitous AMP overexpression reduced fly lifespan alongside induction of mitochondrial stress. A recent study of the AMP gene Metchnikowin further suggests a trade-off between greater antimicrobial activity and host fitness ( Perlmutter et al, 2023 ). These results suggest AMPs could be deleterious to host fitness, which is also supported by evolutionary studies showing that AMP deletions segregate in wild populations ( Early et al, 2017 ; Hanson et al, 2019b ).…”

The endosymbiontSpiroplasma poulsoniiincreasesDrosophila melanogasterresistance to pathogens by enhancing iron-sequestration and melanization

“…Finally, symbiotic microorganisms can enhance host resistance against pathogens and parasites by stimulating or priming the host's immune system (29). This mechanism has been suggested to mediate the host protection by Wolbachia against viruses and certain bacteria (18,30), and potentially against fungi (17). Some studies indicated that Spiroplasma may also induce immune responses in fruit flies, particularly the Toll pathway (19,31).…”

“…Some facultative endosymbionts also bring ecological advantages to their hosts, such as tolerance to heat (6) or protection against natural enemies (7)(8)(9), which also contributes to the maintenance and spread of defensive symbionts in insect populations (10)(11)(12). Symbiont-mediated defense has been confirmed in diverse insects, protecting them against a variety of antagonists, like RNA viruses, nematodes and parasitic wasps, and pathogenic fungi (9,10,(13)(14)(15)(16)(17)(18)(19). The fact that taxonomically different symbionts can provide protection against various parasites suggests that the defensive nature of insect-microbe symbiosis is a common, if not predominant, aspect of insect symbioses.…”