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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-kappaB) pathway. Since the TIR-NF-kappaB 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-kappaB 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-kappaB protein Dif, usually needed for responses against Gram-positive bacteria. CONCLUSIONS/SIGNIFICANCE: Our results show that NO release through STS may reflect an evolutionary conserved process. Moreover, STS could be explored to address immune phenotypes related to infection and may offer ways to boost natural immunity.

Original publication




Journal article


PLoS One

Publication Date





Animals, Anti-Infective Agents, Antimicrobial Cationic Peptides, Drosophila Proteins, Drosophila melanogaster, Enzyme Inhibitors, Gram-Negative Bacterial Infections, Humans, Mice, NF-kappa B, NG-Nitroarginine Methyl Ester, Nitric Oxide, Nitric Oxide Synthase, Signal Transduction, Starvation, Survival Rate, Transcription Factors