Innate defenses protect the host against the activities of several A. fumigatus mycotoxins

Author:

Rui Xu1-2,, Chuqin Huang1 , Rong Yan1, Yanyan Lou1-2, Bo Zhang1, Yingyi Pan1, Yingying Liu1, Sini Huang1, Zhiyuan Zhang1, Antonin Tidu2, Thorsten Heinekamp3, Philippe Bulet4, Franck Martin2, , Axel Brakhage3, Li Zi1, Samuel Liegeois1-2, Dominique Ferrandon* 1-2

Author address:

1 Sino-French Hoffmann Institute, Guangzhou Medical University, Guangzhou, China
2 Université de Strasbourg, IBMC du CNRS, Strasbourg, France
3 Department of Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology – Hans Knöll Institute (Leibniz-HKI), 07745 Jena, Germany
4 CR Université Grenoble Alpes, Institute for Advanced Biosciences, Inserm U1209, CNRS UMR 5309, Grenoble, France; Platform BioPark Archamps, Saint-Julien en Genevois, France

Abstract:

The current paradigm in Drosophila is that upon sensing infections NF-kappaB pathways, Toll and/or Immune deficiency, are activated in the fat body and induce the expression of antimicrobial peptide (AMP) genes. The AMPs secreted in the hemolymph directly attack the invading microbes. This model is supported by genetic data, at least as regards Gram-negative bacterial infections. The situation is less clear with respect to Gram-positive bacterial and fungal infections, which are countered by the Toll response that regulates the expression of some 250 genes. Toll-dependent families of short secreted peptides include Bomanins. Interestingly, the deletion of 10 Bomanin genes at the 55C locus largely phenocopies the Toll mutant susceptibility phenotype (fungal and Gram-positive pathogens).
In contrast to other infections, we report that Aspergillus fumigatus, which kills only Toll-deficient flies and 55C deletion flies, does not proliferate nor disseminate in wild-type or Toll mutant flies. We have identified two A. fumigatus mycotoxins that kill solely immuno-deficient flies and contribute to A. fumigatus virulence. One is a ribotoxin that efficiently cleaves 28S RNA in vivo only in immunodeficient flies; the second mycotoxin, verruculogen, affects the nervous system and induces tremors in all flies: only wild-type flies are able to recover from seizures. These different noxious effects are countered by distinct sets of Bomanins specific to each mycotoxin, BomS6 being able to counteract both types of toxins when overexpressed in neurons.
We have performed a large-scale genetic screen in which we have identified genes that when silenced ubiquitously at the adult stage led to a susceptibility to A. fumigatus infections whereas other lines did not succumb, like wild-type. Out of some 6500 screened lines, about half of the coding genome, we have selected some 50 lines that reproducibly exhibit a deficient survival to A. fumigatus challenge. Most of these lines do not belong to the “canonical” Toll pathway and exhibit a sensitivity to one or the other mycotoxin when silenced ubiquitously and at times when silenced either solely in neurons or only in glial cells.
Three independent examples (Xu et al., Huang et al., unpublished) studied in our team underscore a novel key concept to understand host innate defense against infections: evolution is able to select short secreted peptides to effectively neutralize and/or counteract the actions of different types of secreted microbial virulence factors, a novel aspect of resilience also known as disease tolerance. The genes we have identified in our large-scale genetic screen participate in this resilience facet of host defense. It is an open possibility that such counter-virulence strategies are also at work in mammals.
Xu, R., Lou, Y., Tidu, A., Bulet, P., Heinekamp, T., Martin, F., Brakhage, A., Li, Z., Liegeois, S., and Ferrandon, D. (2023). The Toll pathway mediates Drosophila resilience to Aspergillus mycotoxins through specific Bomanins. EMBO Rep 24, e56036.
Huang, J., Lou, Y., Liu, J., Bulet, P., Cai, C., Ma, K., Jiao, R., Hoffmann, J.A., Liegeois, S., Li, Z., et al. (2023). A Toll pathway effector protects Drosophila specifically from distinct toxins secreted by a fungus or a bacterium. Proc Natl Acad Sci U S A 120, e2205140120.

Abstract Number: 75

Conference Year: 2024

Conference abstracts, posters & presentations

Showing 10 posts of 17325 posts found.

  • Title

    Author

    Year

    Number

    Poster