Insights into the host factors and mechanisms mediating the primary host responses after pathogen presentation remain limited, due in part to the complexity and genetic intractability of host systems. Here, we employ the model Drosophila melanogaster to dissect and identify early host responses that function in the initiation and progression of Pseudomonas aeruginosa pathogenesis. First, we use immune potentiation and genetic studies to demonstrate that flies mount a heightened defense against the highly virulent P. aeruginosa strain PA14 when first inoculated with strain CF5, which is avirulent in flies; this effect is mediated via the Imd and Toll signaling pathways. Second, we use wholegenome expression profiling to assess and compare the Drosophila early defense responses triggered by the PA14 vs. CF5 strains to identify genes whose expression patterns are different in susceptible vs. resistant host-pathogen interactions, respectively. Our results identify pathogenesis-and defense-specific genes and uncover a previously undescribed mechanism used by P. aeruginosa in the initial stages of its host interaction: suppression of Drosophila defense responses by limiting antimicrobial peptide gene expression. These results provide insights into the genetic factors that mediate or restrict pathogenesis during the early stages of the bacterial-host interaction to advance our understanding of P. aeruginosa-human infections.innate immunity ͉ pathogenesis ͉ Drosophila melanogaster ͉ immune potentiation T he innate immunity system, which first evolved in lower animals, is ancestral and, unlike adaptive immunity, occurs throughout invertebrate and vertebrate species. Current knowledge of this system remains limited, especially with regard to the host defense mechanisms used upon initial pathogen presentation. Innate immunity must act quickly to mount a first line of defense to hold the pathogen in check before the adaptive response matures (1). Although defense strategies are diverse for different pathogens, many of them are evolutionarily conserved, including production of an array of antimicrobial peptides (AMPs), activation of phagocytic cells, and production of toxic metabolites. AMPs, the best-studied defense effectors, are rapidly elicited after microbe presentation. These ancient weapons play crucial roles in combating microbial infections in invertebrates, vertebrates, and plants (2).Drosophila has emerged as an ideal model organism to study the genetic control of immune recognition and response, because of the high degree of conservation between the fly and mammalian innate immune systems (3), along with its genetic tractability and simplicity. The Drosophila genome contains at least 15 AMP genes that encode both broad-spectrum antibiotic peptides and more specialized activities against Gram-negative bacteria or fungi (4). Expression of many of these defense effectors is mediated via activation of the Toll and͞or Imd innate immunity signaling pathways (5).We (6) and others (7-9) have used Drosophila to explore th...