Abstract
Toll mediates a robust and effective innate immune response across vertebrates and invertebrates. In Drosophila melanogaster, activation of Toll by systemic infection drives the accumulation of a rich repertoire of immune effectors in hemolymph, including the recently characterized Bomanins, as well as the classical antimicrobial peptides (AMPs). Here we report the functional characterization of a Toll-induced hemolymph protein encoded by the bombardier (CG18067) gene. Using the CRISPR/Cas9 system to generate a precise deletion of the bombardier transcriptional unit, we found that Bombardier is required for Toll-mediated defense against fungi and Gram-positive bacteria. Assaying cell-free hemolymph, we found that the Bomanin-dependent candidacidal activity is also dependent on Bombardier, but is independent of the antifungal AMPs Drosomycin and Metchnikowin. Using mass spectrometry, we demonstrated that deletion of bombardier results in the specific absence of short-form Bomanins from hemolymph. In addition, flies lacking Bombardier exhibited a defect in pathogen tolerance that we trace to an aberrant condition triggered by Toll activation. These results lead us to a model in which the presence of Bombardier in wild-type flies enables the proper folding, secretion, or intermolecular associations of short-form Bomanins, and the absence of Bombardier disrupts one or more of these steps, resulting in defects in both immune resistance and tolerance.
Highlights
Innate immune pathways are found in plants, fungi, and animals and provide a rapid defense against a broad range of pathogens [1,2,3]
Two additional genotypes were used as controls: w1118 flies, which served as the wild type, and Bomanin peptides (Boms) 55C flies, which lack Toll-mediated humoral defenses due to deletion of the 10 of the 12 Bom genes [24]
The results presented in this study identify a key factor that regulates humoral and Bom-mediated defense in Drosophila
Summary
Innate immune pathways are found in plants, fungi, and animals and provide a rapid defense against a broad range of pathogens [1,2,3]. The Toll pathway is activated by Gram-positive bacteria with Lys-type peptidoglycan and by fungi, and is required for defense against these microbes [7,8,9,10]. The Imd pathway is activated by and plays a major role in survival against Gram-negative bacteria and Gram-positive bacteria with DAP-type peptidoglycan [11, 12]. These pathways, which are both mediated by NF-κB transcription factors, are broadly conserved as initiators of innate immune responses. Activation of either pathway induces robust production of an array of immune molecules, including antimicrobial peptides (AMPs) [13,14,15,16,17]
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