Drosophila melanogaster is a powerful host model to study mycobacterial virulence

Abstract

Drosophila melanogaster (Drosophila), the common fruit fly, is one of the most extensively studied animal models we have, with a broad, advanced, and organized research community with tools and mutants readily available at low cost. Yet, Drosophila has barely been exploited to understand the underlying mechanisms of mycobacterial infections, including those caused by the top-killer pathogen Mycobacterium tuberculosis (Mtb). In this study, we aimed to investigate whether Drosophila is a suitable host model to study mycobacterial virulence, using Mycobacterium marinum (Mmar) to model mycobacterial pathogens. First, we validated that an established mycobacterial virulence factor, EccB1 of the ESX-1 Type VII secretion system, is required for Mmar growth within the flies. Second, we identified Mmar virulence factors in Drosophila in a high-throughput genome-wide manner using transposon insertion sequencing (TnSeq). Of the 181 identified virulence genes, the vast majority (91%) had orthologs in Mtb, suggesting that the encoded virulence mechanisms may be conserved across Mmar and Mtb. Finally, we validated one of the novel Mmar virulence genes we identified, a putative ATP-binding protein ABC transporter encoded by mmar_1660, as required for full virulence during both Drosophila and human macrophage infection. Together, our results show that Drosophila is a powerful host model to study and identify novel mycobacterial virulence factors relevant to human infection.