Responses of the immune systems of plants and animals show what appears to be evidence of ancient attacks and counterattacks by pathogens and their hosts in the battle for survival. Drosophila have developed receptors that recognize constituents of bacterial cell walls and mount an immune response that causes proteolytic cleavage of the cytokine Spätzle. The Spätzle fragment then activates Toll receptors and leads to production of antimicrobial peptides. Gottar et al. explored the response of Drosophila to fungal infections and found a similar defense mechanism but also unveiled a second signaling pathway that detects a virulence factor produced by the fungus. The authors infected flies by pricking them with a needle dipped in fungus-containing solution and monitored survival or Toll-dependent expression of the gene encoding an antifungal peptide. They found that the receptor GNBP3 (Gram-negative binding protein 3) was required for detection of cell wall components of the fungi and consequent activation of Toll receptors. However, cells with a mutated GNB3 protein could still respond to fungi and activate Toll, but in this case cell wall-derived components were not the trigger. This response depended on the presence of live fungi and, presumably, the production of virulence factors. One such factor is the protease PR1, and the authors showed that expression of PR1 alone led to activation of the Toll pathway. Knowing that a fly protease PSH (Persephone), which is thought to participate in a cascade of proteases that lead to Spätzle cleavage and activation of the Toll pathway in response to fungi, itself requires proteolytic removal of a prodomain for activity, the authors tested whether PR1 might activate PSH. Indeed, studies in vitro and in vivo indicated that PSH appears to be a direct substrate of PR1. The fungi use the PR1 protease to break down the protective cuticle of the insect and allow infection. The authors propose that PSH acts like a sensor to monitor the status of the cuticle. If the presence of PR1 shows that the defense barrier is being broken, PSH is cleaved and the antimicrobial signaling is initiated. Whether humans have such a sensor system to recognize fungal virulence factors remains unknown.M. Gottar, V. Gobert, A. A. Matskevich, J.-M. Reichhart, C. Wang, T. M. Butt, M. Belvin, J. A. Hoffmann, D. Ferrandon, Dual detection of fungal infections in Drosophila via recognition of glucans and sensing of virulence factors. Cell127, 1425-1437 (2006). [Online Journal]
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