Prevalence of Local Immune Response against Oral Infection in a Drosophila/Pseudomonas Infection Model

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Abstract
Pathogens have developed multiple strategies that allow them to exploit host resources and resist the immune response. To study how Drosophila flies deal with infectious diseases in a natural context, we investigated the interactions between Drosophila and a newly identified entomopathogen, Pseudomonas entomophila. Flies orally infected with P. entomophila rapidly succumb despite the induction of both local and systemic immune responses, indicating that this bacterium has developed specific strategies to escape the fly immune response. Using a combined genetic approach on both host and pathogen, we showed that P. entomophila virulence is multi-factorial with a clear differentiation between factors that trigger the immune response and those that promote pathogenicity. We demonstrate that AprA, an abundant secreted metalloprotease produced by P. entomophila, is an important virulence factor. Inactivation of aprA attenuated both the capacity to persist in the host and pathogenicity. Interestingly, aprA mutants were able to survive to wild-type levels in immune-deficient Relish flies, indicating that the protease plays an important role in protection against the Drosophila immune response. Our study also reveals that the major contribution to the fly defense against P. entomophila is provided by the local, rather than the systemic immune response. More precisely, our data points to an important role for the antimicrobial peptide Diptericin against orally infectious Gram-negative bacteria, emphasizing the critical role of local antimicrobial peptide expression against food-borne pathogens. Normal feeding and digestion involves the ingestion of many microorganisms. Many are innocuous, some are commensal, and others may be pathogenic. Eukaryotes have thus evolved complex mechanisms to detect, control, and if necessary, eliminate intestinal microbes. Insects are no exception, and the fruit fly, Drosophila, employs a physical barrier within the intestinal lumen and the peritrophic matrix, and an innate immune response which exhibits similarities to the mammalian counterpart. Pseudomonas entomophila was identified as a novel entomopathogenic bacterium that can infect and colonize the gut of Drosophila. In this paper, Liehl et al. describe one specific secreted virulence factor of P. entomophila, the zinc metalloprotease, AprA, which they demonstrate to be required for defense against the host gut epithelial immune response. AprA defends P. entomophila against the Drosophila antimicrobial peptides, produced by the gut innate immune response. P. entomophila aprA mutants are attenuated for virulence in wild-type Drosophila but are equally infective as wild-type bacteria in immune-deficient mutant flies that do not express these antimicrobial peptides. Although secreted proteases have previously been described as a potentially important defense against host immune proteins, this is one of the rare examples of an in vivo demonstration of such a specific role against insect antimicrobial peptides.

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