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Arthropod vectors are important vehicles for transmission ofFrancisella tularensisbetween mammals, but very little is known about theF. tularensis–arthropod vector interaction.Drosophila melanogasterhas been recently developed as an arthropod vector model forF. tularensis.We have shown that intracellular trafficking ofF. tularensiswithin human monocytes-derived macrophages andD. melanogaster-derived S2 cells is very similar. Within both evolutionarily distant host cells, theFrancisella-containing phagosome matures to a late endosome-like phagosome with limited fusion to lysosomes followed by rapid bacterial escape into the cytosol where the bacterial proliferate. To decipher the molecular bases of intracellular proliferation ofF. tularensiswithin arthropod-derived cells, we screened a comprehensive library of mutants ofF. tularensisssp.novicidafor their defect in intracellular proliferation withinD. melanogaster-derived S2 cells. Our data show that 394 genes, representing 22% of the genome, are required for intracellular proliferation withinD. melanogaster-derived S2 cells, including many of theFrancisellaPathogenicity Island (FPI) genes that are also required for proliferation within mammalian macrophages. Functional gene classes that exhibit growth defect include metabolic (25%), FPI (2%), type IV pili (1%), transport (16%) and DNA modification (5%). Among 168 most defective mutants in intracellular proliferation in S2 cells, 80 are defective in lethality and proliferation within adultD. melanogaster.The observation that only 135 of the 394 mutants that are defective in S2 cells are also defective in human macrophages indicates thatF. tularensisutilize common as well as distinct mechanisms to proliferate within mammalian and arthropod cells. Our studies will facilitate deciphering the molecular aspects ofF. tularensis–arthropod vector interaction and its patho-adaptation to infect mammals.