The Whole Animal Model Drosophila melanogaster

D. melanogaster mount both cellular and humoral immune responses to pathogens. The innate immune response of the fruit fly D. melanogaster is characterized by a cellular immune response which depends on circulating phagocytic cells, a melanization response which produces reactive oxygen species at sites of infection, and the production ofantimicrobial peptides in the fat body. D. melanogaster lacks an antibody-mediated adaptive immune response [52], but can react to different kinds of infections caused by Gram-positive or Gram-negative bacteria, fungi or parasitic protozoa. The sequencing of the entire genome revealed that a set of around 14000 genes is sufficient for the generation of a multicellular organism of this kind that is able to perform complex immunogenic reactions [53]. Several thousand mutant fly strains with defects in one defined gene each are available for the genetic dissection of traits (http://flybase.net).

Most studies on the host-pathogen interaction with whole animals use injection methods to directly challenge the immune system, since only few pathogens are capable of naturally infecting D. melanogaster. Upon infection, a signaling cascade is activated which leads to the production of antimicrobial peptides in the fat body of the fly. It turned out that the activation of peptide production depends mainly on two distinct signal transduction pathways, the Toll and IMD (immune deficiency) pathways. Both pathways share striking similarities with the innate immune response pathways of mammals [52]. This innate immune system is activated differently depending on the nature of the attacker, thus discriminating between different classes of pathogens: fungi and Gram-positive bacteria induce the Toll pathway, whereas Gram-negative bacteria are sensed by the IMD pathway. Other signaling pathways, such as the JAK-STAT and the JNK pathways, may also be involved in the immune response, although the exact contribution ofthese pathways is not yet clear [54].

The most prominent pathogen studied in D. melanogaster is P. aeruginosa. Its virulence factors required for full infectivity in D. melanogaster are the same as for mammals. Moreover, the fact that the type III protein secretion system is activated during infection of both mammals and Drosophila recommends the fruit fly as a real in vivo model for the molecular dissection of virulence factor functions. Further virulence factors relevant in D. melanogaster are the GacAS two-component system, phenazine pigments, exotoxin A, as well as type IV pili [55]. Other pathogens currently under investigation in the fruit fly model are Serratia marcescens, L. monocytogenes and M. marinum. In adult flies, M. marinum initially infects hemocytes, where it blocks vacuolar acidification and replicates intracellularly [56]. M. marinum lacking the mag24 gene is less virulent for D. melanogaster, similar to what has been observed for infections of D. discoideum [57]. Remarkably, phag1 mutants, both in D. melanogaster and D. discoideum, also exhibit a specific susceptibility to Klebsiella pneumoniae.

Infections with fungi can also be monitored in D. melanogaster. In one study the authors infected immune-deficient flies with different Candida albicans mutants. Virulence patterns against D. melanogaster in these strains reproduced those in a murine model. Importantly, using this insect model they found additional virulence properties undetectable in the murine system [58]. Taken together, these studies support the hypothesis that evolutionary distant eukaryotic organisms share conserved strategies for resistance to infections.

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