TheDrosophila melanogasterToll Pathway Participates in Resistance to Infection by the Gram-Negative Human PathogenPseudomonas aeruginosa

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Abstract
Pseudomonas aeruginosais a gram-negative pathogen that infects immunocompromised and cystic fibrosis patients. The molecular basis of the host-P. aeruginosainteraction and the effect of specificP. aeruginosavirulence factors on various components of the innate immunity pathways are largely unknown. We examine interactions betweenP. aeruginosavirulence factors and components of innate immunity response in theDrosophila melanogastermodel system to reveal the importance of the Toll signaling pathway in resistance to infection by theP. aeruginosahuman isolate PA14. Using the two PA14-isogenic mutantsplcSanddsbA, we show thatDrosophilaloss-of-function mutants of Spatzle, the extracellular ligand of Toll, and Dorsal and Dif, two NF-κB-like transcription factors, allow increasedP. aeruginosainfectivity within fly tissues. In contrast, a constitutively active Toll mutant and a loss-of-function mutant of Cactus, an IκB-like factor that inhibits the Toll signaling, reduce infectivity. Our finding that Dorsal activity is required to restrictP. aeruginosainfectivity inDrosophilaprovides direct in vivo evidence for Dorsal function in adult fly immunity. Additionally, our results provide the basis for future studies into interactions betweenP. aeruginosavirulence factors and components of the Toll signaling pathway, which is functionally conserved between flies and humans.