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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI083932-05
Application #
8490287
Study Section
Genetic Variation and Evolution Study Section (GVE)
Program Officer
Leitner, Wolfgang W
Project Start
2011-07-01
Project End
2016-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2013
Total Cost
$355,381
Indirect Cost
$120,381
Name
Cornell University
Department
Zoology
Type
Schools of Earth Sciences/Natur
DUNS #
872612445
City
Ithaca
State
NY
Country
United States
Zip Code
14850
Howick, Virginia M; Lazzaro, Brian P (2017) The genetic architecture of defence as resistance to and tolerance of bacterial infection in Drosophila melanogaster. Mol Ecol 26:1533-1546
Lazzaro, Brian P; Fox, Gabriel M (2017) Host-Microbe Interactions: Winning the Colonization Lottery. Curr Biol 27:R642-R644
Schwenke, Robin A; Lazzaro, Brian P (2017) Juvenile Hormone Suppresses Resistance to Infection in Mated Female Drosophila melanogaster. Curr Biol 27:596-601
Duneau, David F; Kondolf, Hannah C; Im, Joo Hyun et al. (2017) The Toll pathway underlies host sexual dimorphism in resistance to both Gram-negative and Gram-positive bacteria in mated Drosophila. BMC Biol 15:124
Akhund-Zade, Jamilla; Bergland, Alan O; Crowe, Sarah O et al. (2017) The Genetic Basis of Natural Variation in Drosophila (Diptera: Drosophilidae) Virgin Egg Retention. J Insect Sci 17:
Duneau, David; Ferdy, Jean-Baptiste; Revah, Jonathan et al. (2017) Stochastic variation in the initial phase of bacterial infection predicts the probability of survival in D. melanogaster. Elife 6:
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
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

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