Nutritional factors can have profound influence on immune defense, but the mechanisms linking dietary nutrition to immunity are poorly understood. Work performed under the proposed project will establish the relationship between nutrition and defense from physiological and genetic perspectives, and will ultimately identify genes contributing to individual-specific alteration in immunity due to diet. The project will make use of the model insect Drosophila melanogaster, which has metabolic and immune systems that are highly conserved with homologous systems in vertebrates.
In Aim 1 of the project, D. melanogaster provided with diets of varying nutritional composition will be evaluated for resistance to bacterial infection (measured as immune system activity and suppression of bacterial proliferation) and tolerance of infection (measured as the ability to sustain health while infected). The experimental diets to be evaluated will vary in protein, sugar and fat levels.
Aim 2 of the project will test the hypothesis that specific immune and metabolic signaling pathways are linked during infection, such that activation of the immune system causes altered metabolism and energetic utilization. The IMD (immune system), JNK (stress response), and insulin-like (metabolism) signaling pathways will be genetically disrupted to test for cross-communication between processes during the early stages of an infection.
Aim 3 of the project will conceptually link the first two Aims in a study of naturally occurring variation. It is known that individuals in natural populations are genetically variable for both immune-related and metabolic traits. Experiments to be performed under Aim 3 will determine the degree to which resistance and tolerance phenotypes are determined by genotype-specific effects of diet (termed genotype-by-environment interaction). These interactions form the conceptual basis of personalized medicine, and understanding them will be crucial for advanced clinical therapeutics. Analysis of known polymorphisms and unbiased genome-wide association mapping will be employed to identify genes responsible for genotype-specific immunological alteration with diet. The data collected under all three Aims will provide novel and broadly comprehensive understanding of dietary effects on defense quality, with critical implications for clinical and evolutionary biology.

Public Health Relevance

It is intuitively appreciated that dietary nutrition can influence resistance to infection, but the mechanisms connecting nutrition to defense are poorly understood. The proposed study will evaluate the impact of dietary nutrients on immune defense, will determine the genetic mechanisms linking nutrition and defense, and will identify genes contributing to individual-specific alterations in immunity attributable to diet. The work will contribute to understanding disease resistance and susceptibility in evolutionary and clinically relevant contexts.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Study Section
Genetic Variation and Evolution Study Section (GVE)
Program Officer
Leitner, Wolfgang W
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Cornell University
Schools of Earth Sciences/Natur
United States
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Unckless, Robert L; Howick, Virginia M; Lazzaro, Brian P (2016) Convergent Balancing Selection on an Antimicrobial Peptide in Drosophila. Curr Biol 26:257-62
Schwenke, Robin A; Lazzaro, Brian P; Wolfner, Mariana F (2016) Reproduction-Immunity Trade-Offs in Insects. Annu Rev Entomol 61:239-56
Unckless, Robert L; Rottschaefer, Susan M; Lazzaro, Brian P (2015) A genome-wide association study for nutritional indices in Drosophila. G3 (Bethesda) 5:417-25
Unckless, Robert L; Rottschaefer, Susan M; Lazzaro, Brian P (2015) The complex contributions of genetics and nutrition to immunity in Drosophila melanogaster. PLoS Genet 11:e1005030
Dobson, Adam J; Chaston, John M; Newell, Peter D et al. (2015) Host genetic determinants of microbiota-dependent nutrition revealed by genome-wide analysis of Drosophila melanogaster. Nat Commun 6:6312
Lazzaro, Brian P (2015) Adenosine signaling and the energetic costs of induced immunity. PLoS Biol 13:e1002136
Khalil, Sarah; Jacobson, Eliana; Chambers, Moria C et al. (2015) Systemic bacterial infection and immune defense phenotypes in Drosophila melanogaster. J Vis Exp :e52613
Lazzaro, Brian P; Schneider, David S (2014) The genetics of immunity. Genetics 197:467-70
Howick, Virginia M; Lazzaro, Brian P (2014) Genotype and diet shape resistance and tolerance across distinct phases of bacterial infection. BMC Evol Biol 14:56
Chambers, Moria C; Jacobson, Eliana; Khalil, Sarah et al. (2014) Thorax injury lowers resistance to infection in Drosophila melanogaster. Infect Immun 82:4380-9

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