The Toll pathway mediates <i>Drosophila</i> resilience to <i>Aspergillus</i> mycotoxins through specific Bomanins

Xu, Rui; Lou, Yanyan; Tidu, Antonin; Bulet, Philippe; Heinekamp, Thorsten; Martin, Franck; Brakhage, Axel A.; Li, Zi; Liegois, Samuel; Ferrandon, Dominique

doi:10.1101/2022.08.18.504437

Cited by 3 publications

(3 citation statements)

References 71 publications

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“…In this last case, we imagine that functional Mtk might interact with the pathogen in some complex way to enhance mortality. This may be through interaction with pleiotropic functions of Mtk in the brain [46][47][48] , or through negative regulatory or direct interactions with secreted fungal molecules, which can occur with Mtk and other AMPs 64,65 . This suggests that host outcomes depend on a complex set of factors including pathogen identity and host genotype and the exact mechanism of functional differences may not simply be one allele being more potent against microbes.…”

Section: Discussionmentioning

confidence: 99%

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

Perlmutter

Chapman²,

Wilkinson

et al. 2023

Preprint

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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.

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Section: Discussionmentioning

confidence: 99%

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

Perlmutter

Chapman²,

Wilkinson

et al. 2023

Preprint

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“…When expressed with the BomS3 promoter, BomS6 was not susceptible to C. glabrata infection, but BomT2 showed no difference in susceptibility. Xu et al [3] showed that BomBc1, BomS3 and BomS4 were significantly induced upon A. fumigatus infection and that, as a whole, the Bomanin cluster enhances both resistance to, and tolerance of, infection with A. fumigatus. BomBc1, BomS3 and BomS6 increased tolerance to the fungal toxin, restrictocin, whereas Bom S6 and BomS1 increased tolerance to another toxin, verruculogen.…”

Section: Discussionmentioning

confidence: 99%

“…Several recent studies have attempted to characterize the role of individual Bomanin genes, the entire cluster of 10 genes, or subsets of those genes (summarized in Table 1) [1-3, 26, 46]. This began with Clemmons et al .…”

Section: Discussionmentioning

confidence: 99%

The genetic basis of variation immune defense againstLysinibacillus fusiformisinfection inDrosophila melanogaster

Smith

Patch

Unckless

2022

Preprint

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The genetic causes of phenotypic variation often differ depending on the population examined, particularly if the populations were founded by relatively small numbers of genotypes. Similarly, the genetic causes of phenotypic variation among similar traits (resistance to different xenobiotic compounds or pathogens) may also be completely different or only partially overlapping. Differences in genetic causes for variation in the same trait among populations suggests considerable context dependence for how selection might act on those traits. Similarities in the genetic causes of variation for different traits, on the other hand, suggests pleiotropy which also would influence how natural selection would shape variation in a trait. We characterized immune defense against a naturalDrosophilapathogen, the Gram-positiveLysinibacillus fusiformis, in three different populations and found almost no overlap in the genetic architecture of variation in survival post infection. However, when comparing our results to a similar experiment with the fungal pathogen,B. bassiana, we found a convincing shared QTL peak for both pathogens. This peak contains theBomanincluster ofDrosophilaimmune effectors. RNAi knockdown experiments confirms a role of some of these genes in immune defense against both pathogens. This suggests that natural selection may act on the entire cluster ofBomaningenes (and the linked region under the QTL) or specific peptides for specific pathogens.Author SummaryLike most traits, the way individuals respond to infection vary among individuals within a population. Some of this variation is caused by genetic differences in the host organism. Over the past decade, two prominent resources were developed to assess genetic variation for complex traits of the fruit fly,Drosophila melanogasterand map the genetic variants responsible. We recently described a strain ofLysinibacillus fusiformisbacteria, which was isolated from fruit flies and is moderately virulent when flies are infected. We mapped genetic variation in resistanceL. fusiformisusing these mapping resources. We find that among the resources, different changes were associated with immune defense. However, we also found that within a resource, the same region of the genome was associated with resistance to bothL. fusiformisand a fungal pathogen. These results suggest that different populations adapt differently to the same pathogens, but two distinct pathogens share similar causes of genetic variation within a single population.

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A Toll pathway effector protects Drosophila specifically from distinct toxins secreted by a fungus or a bacterium

Huang

Lou

Liu

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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The Drosophila systemic immune response against many Gram-positive bacteria and fungi is mediated by the Toll pathway. How Toll-regulated effectors actually fulfill this role remains poorly understood as the known Toll-regulated antimicrobial peptide (AMP) genes are active only against filamentous fungi and not against Gram-positive bacteria or yeasts. Besides AMPs, two families of peptides secreted in response to infectious stimuli that activate the Toll pathway have been identified, namely Bomanins and peptides derived from a polyprotein precursor known as Baramicin A (BaraA). Unexpectedly, the deletion of a cluster of 10 Bomanins phenocopies the Toll mutant phenotype of susceptibility to infections. Here, we demonstrate that BaraA is required specifically in the host defense against Enterococcus faecalis and against the entomopathogenic fungus Metarhizium robertsii , albeit the fungal burden is not altered in BaraA mutants. BaraA protects the fly from the action of distinct toxins secreted by these Gram-positive and fungal pathogens, respectively, Enterocin V and Destruxin A. The injection of Destruxin A leads to the rapid paralysis of flies, whether wild type (WT) or mutant. However, a larger fraction of wild-type than BaraA flies recovers from paralysis within 5 to 10 h. BaraAs' function in protecting the host from the deleterious action of Destruxin is required in glial cells, highlighting a resilience role for the Toll pathway in the nervous system against microbial virulence factors. Thus, in complement to the current paradigm, innate immunity can cope effectively with the effects of toxins secreted by pathogens through the secretion of dedicated peptides, independently of xenobiotics detoxification pathways.

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The Toll pathway mediates Drosophila resilience to Aspergillus mycotoxins through specific Bomanins

Cited by 3 publications

References 71 publications

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

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

The genetic basis of variation immune defense againstLysinibacillus fusiformisinfection inDrosophila melanogaster

A Toll pathway effector protects Drosophila specifically from distinct toxins secreted by a fungus or a bacterium

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