The Role of Anorexia in Resistance and Tolerance to Infections in Drosophila

Department of Microbiology and Immunology, Stanford University, Stanford, California, USA.
PLoS Biology (Impact Factor: 9.34). 08/2009; 7(7):e1000150. DOI: 10.1371/journal.pbio.1000150
Source: PubMed


Author Summary
Two routes to decreasing susceptibility to infection are resistance (the ability to clear pathogens) and tolerance (the ability to limit damage in response to pathogens). Anorexia induced by sickness puts animals into a diet-restricted state, a state that is generally believed to extend lifespan. We asked whether anorexia induced by sickness would alter the immune response. We measured the effects of diet restriction on both resistance and tolerance to two different infections in the fruit fly, Drosophila melanogaster. In one case we found that infection induced anorexia and the resulting diet restriction increased tolerance to this infection, thereby increasing survival of flies infected with this pathogen; however, this is not a universal effect. In a second case we found another pathogen that induced anorexia but here diet restriction lead to a reduction in resistance that collapsed the immune response and caused the fly to die faster. The relationship between diet restriction and immunity is complicated and must be evaluated on a pathogen-by-pathogen basis.

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Available from: David Schneider, Jun 28, 2015
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    • "Our current model as well as previous data suggests that immune competence is an important determinant of fitness, but costly to the host requiring trade-offs with other energy demanding processes such as growth and reproduction[15,1819202122. When we measured glucose content in flies surviving sepsis, flies surviving sepsis had significantly lower stores of glucose compared to sham and increased lactate levels, yet similar ATP contents in both groups[15,2324252627. Sepsis, the epitome of a complex relation between pathogen and host, is energetically expensive and results in maladaptive allocation of resources away from growth to antimicrobial response, akin to the preferred aerobic glycolysis over oxidative phosphorylation seen in cancer cells[7,23,28,29]. "
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    ABSTRACT: Multiple organ failure, wasting, increased morbidity, and mortality following acute illness complicates the health span of patients surviving sepsis. Persistent inflammation has been implicated, and it is proposed that insulin signaling contributes to persistent inflammatory signaling during the recovery phase after sepsis. However, mechanisms are unknown and suitable pre-clinical models are lacking. We therefore developed a novel Drosophila melanogaster model of sepsis to recapitulate the clinical course of sepsis, explored inflammation over time, and its relation to impaired mobility, metabolic disturbance, and changes in lifespan. We used wild-type (WT), Drosomycin-green fluorescent protein (GFP), and NF-κB-luc reporter male Drosophila melanogaster 4–5 days of age (unmanipulated). We infected Drosophila with Staphylococcus aureus (infected without treatment) or pricked with aseptic needles (sham). Subsets of insects were treated with oral linezolid after the infection (infected with antibiotics). We assessed rapid iterative negative geotaxis (RING) in all the groups as a surrogate for neuromuscular functional outcome up to 96 h following infection. We harvested the flies over the 7-day course to evaluate bacterial burden, inflammatory and metabolic pathway gene expression patterns, NF-κB translation, and metabolic reserve. We also followed the lifespan of the flies. Our results showed that when treated with antibiotics, flies had improved survival compared to infected without treatment flies in the early phase of sepsis up to 1 week (81 %, p = 0.001). However, the lifespan of infected with antibiotics flies was significantly shorter than that of sham controls (p = 0.001). Among infected with antibiotic sepsis survivors, we observed persistent elevation of NF-κB in the absence of any obvious infection as shown by culturing flies surviving sepsis. In the same group, geotaxis had an early (18 h) and sustained decline compared to its baseline. Geotaxis in infected with antibiotics sepsis survivors was significantly lower than that in sham and age-matched unmanipulated flies at 18 and 48 h. Expression of antimicrobial peptides (AMP) remained significantly elevated over the course of 7 days after sepsis, especially drosomycin (5.7-fold, p = 0.0145) on day 7 compared to that of sham flies. Infected with antibiotics flies had a trend towards decreased Akt activation, yet their glucose stores were significantly lower than those of sham flies (p = 0.001). Sepsis survivors had increased lactate levels and LDH activity by 1 week, whereas ATP and pyruvate content was similar to that of the sham group. In summary, our model mimics human survivors of sepsis with persistent inflammation, impaired motility, dysregulated glucose metabolism, and shortened lifespan.
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    • "The concept of tolerance (also termed resilience) provides an exciting, novel perspective on pathogenhost interactions in metazoans. A few examples of tolerance to bacterial or viral infections have been described in flies42434445464748, but the mechanisms of tolerance remain largely unknown. In this study, we elucidate a novel epigenetics-based mechanism for tolerance. "
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    ABSTRACT: Author Summary Multicellular organisms deploy various strategies to fight microbial infections. Invading pathogens may be eradicated directly by antimicrobial effectors of the immune system. Another strategy consists of increasing the tolerance of the host to infection, for example, by limiting the adverse effects of the immune response. The molecular mechanisms underlying this novel concept remain largely uncharacterized. Here, we demonstrate that the epigenetic regulator G9a mediates tolerance to virus infection in Drosophila. We found that G9a-deficient flies succumb faster than control flies to infection with RNA viruses, but that the viral burden did not significantly differ. Unexpectedly, mutant flies express higher levels of genes that are regulated by the Jak-Stat signaling pathway, which in other studies was found to be important for antiviral defense. Exploiting the genetic toolbox in Drosophila, we demonstrate that Jak-Stat hyperactivation induces early mortality after virus infection. Precise control of immune pathways is essential to ensure efficient immunity, while preventing damage due to excessive immune responses. Our results indicate that G9a, an epigenetic modifier, dampens Jak-Stat responses to prevent immunopathology. Therefore, we propose epigenetic regulation of immunity as a new paradigm for disease tolerance.
    Full-text · Article · Apr 2015 · PLoS Pathogens
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    • "Although the response of GA cockroaches is driven by gustatory deterrence and is therefore not directly toxin - induced , the feeding response to glucose - contain - ing diets by GA cockroaches is highly comparable to the feeding response observed in animals that are infected with a toxin - producing pathogen . Infected ani - mals typically reduce consumption rate ( Exton , 1997 ; Ayres & Schneider , 2009 ; Adamo et al . , 2010 ) . "
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    ABSTRACT: Animals balance their intake of specific nutrients, but little is known about how they do so when foraging in an environment with toxic resources and whether toxic foods promote adaptations that affect life history traits. In German cockroach (Blattella germanica) populations, glucose aversion has evolved in response to glucose-containing insecticidal baits. We restricted newly eclosed glucose-averse (GA) and wild-type (WT) female cockroaches to nutritionally defined diets varying in protein-to-carbohydrate (P : C) ratio (3 : 1, 1 : 1, or 1 : 3) or gave them free choice of the 3 : 1 and 1 : 3 diets, with either glucose or fructose as the sole carbohydrate source. We mea- sured consumption of each diet over 6 days and then dissected the females to measure the length of basal oocytes in their ovaries. Our results showed significantly lower consumption by GA compared to WT cockroaches when restricted to glucose-containing diets, but also lower fructose intake by GA compared to WT cockroaches when restricted to high fructose diets or given choice of fructose-containing diets. Protein intake was regulated tightly regardless of carbohydrate intake, except by GA cockroaches restricted to glucose-containing diets. Oocyte growth was completely suppressed in GA females restricted to glucose-containing diets, but also significantly slower in GA than in WT females restricted to fructose-containing diets. Our findings suggest that GA cockroaches have adapted to reduced diet breadth through endocrine adjustments which reduce requirements for energetic fuels. Our study illustrates how an evolutionary change in the chemosensory system may affect the evolution of other traits that govern animal life histories.
    Full-text · Article · Jan 2015 · Journal of Evolutionary Biology
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