25.5% of all deaths worldwide can be attributed to infections, suggesting a need for novel therapeutic targets. The mechanisms by which pathogens induce an immune response are well-studied; the ways infections alter metabolism remain largely unexplored. Nevertheless, metabolic dysregulation is clinically observed in a broad range of diseases. The goal of this proposal is to determine the mechanism by which infection disrupts systemic metabolic homeostasis. Understanding the causal relationship between infection and metabolic disruption could lead to novel therapeutics that stabilize metabolism during infection. Here, I propose to use a model of Drosophila melanogaster infected with the bacterial pathogen Listeria monocytogenes. My preliminary analysis identified similar gene expression patterns between infected flies and flies that lack the transcription factor Drosophila Hepatocyte Nuclear Factor 4 (dHNF4). dHNF4 controls insulin signaling and lipid metabolism in mammals as well as invertebrates; these processes are dysregulated in infected flies. The hypothesis driving this work is that dHNF4 mediates the metabolic disruptions that occur in L. monocytogenes-infected flies.
In Aim 1, I propose to determine how infection affects dHNF4 regulation by measuring dHNF4 protein levels, post-translational modifications, and activation during infection.
In Aim 2, I will determine the role of dHNF4 during infection through gain- or loss-of-function experiments.
In Aim 3, I will define the contributions of dHNF4-dependent pathways to infection outcome using an attenuated L. monocytogenes strain. The completion of this work will uncover the relationship between infection and a key metabolic regulator. Furthermore, these studies may inform the development of therapies that target metabolism during infection.

Public Health Relevance

The work described here is relevant to the treatment of infectious diseases. Specifically, it will increase our understanding of the mechanisms by which infection disrupts systemic metabolic homeostasis using a model of Drosophila melanogaster infected with Listeria monocytogenes. Results of this project will inform novel therapeutic approaches that target and stabilize metabolism during infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31AI143002-02
Application #
10073327
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Baqar, Shahida
Project Start
2019-09-23
Project End
2021-09-22
Budget Start
2020-09-23
Budget End
2021-09-22
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Stanford University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305