innate immune responses of drosophila melanogaster are altered by spaceflight alterations and impairment of immune responses in humans present a health risk for space exploration missions the molecular mechanisms underpinning innate immune defense can be confounded by the complexity of the acquired immune system of humans drosophila fruit fly innate immunity is simpler and shares many similarities with human innate immunity at the level of molecular and genetic pathways the goals of this study were to elucidate fundamental immune processes in drosophila affected by spaceflight and to measure hostpathogen responses postflight five containers each containing ten female and five male fruit flies were housed and bred on the space shuttle average orbit altitude of 33035 km for 12 days and 185 hours a new generation of flies was reared in microgravity in larvae the immune system was examined by analyzing plasmatocyte number and activity in culture in adults the induced immune responses were analyzed by bacterial clearance and quantitative realtime polymerase chain reaction qpcr of selected genes following infection with e coli the rna levels of relevant immune pathway genes were determined in both larvae and adults by microarray analysis the ability of larval plasmatocytes to phagocytose e coli in culture was attenuated following spaceflight and in parallel the expression of genes involved in cell maturation was downregulated in addition the level of constitutive expression of pattern recognition receptors and opsonins that specifically recognize bacteria and of lysozymes antimicrobial peptide amp pathway and immune stress genes hallmarks of humoral immunity were also reduced in larvae in adults the efficiency of bacterial clearance measured in vivo following a systemic infection with e coli postflight remained robust we show that spaceflight altered both cellular and humoral immune responses in drosophila and that the disruption occurs at multiple interacting pathways