short-term starvation of immune deficient drosophila improves survival to gram-negative bacterial infections短期饥饿的免疫缺陷果蝇改善生存革兰氏阴性细菌感染.pdfVIP

Short-Term Starvation of Immune Deficient Drosophila Improves Survival to Gram-Negative Bacterial Infections 1,2 1 2 1 Anthony E. Brown , Janina Baumbach , Peter E. Cook , Petros Ligoxygakis * 1 Genetics Unit Department of Biochemistry, University of Oxford, Oxford, United Kingdom, 2 Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, United Kingdom Abstract Background: Primary immunodeficiencies are inborn errors of immunity that lead to life threatening conditions. These predispositions describe human immunity in natura and highlight the important function of components of the Toll-IL-1- receptor-nuclear factor kappa B (TIR-NF-kB) pathway. Since the TIR-NF-kB circuit is a conserved component of the host defence in higher animals, genetically tractable models may contribute ideas for clinical interventions. Methodology/Principal Findings: We used immunodeficient fruit flies (Drosophila melanogaster) to address questions pertaining to survival following bacterial infection. We describe here that flies lacking the NF-kB protein Relish, indispensable for countering Gram-negative bacteria, had a greatly improved survival to such infections when subject to dietary short-term starvation (STS) prior to immune challenge. STS induced the release of Nitric Oxide (NO), a potent molecule against pathogens in flies, mice and humans. Administering the NO Synthase-inhibitory arginine analog N-Nitro-L- Arginine-Methyl-Ester (L-NAME) but not its inactive enantiomer D-NAME increased once again sensitivity to infection to levels expected for relish mutants. Surprisingly, NO signalling required the NF-kB protein Dif, usually needed for res