The metabolic machinery of the cell and the array of immune defense pathways are highly intertwined. Peroxisomes, essential metabolic organelles that manage cellular lipid and redox turnover, were recently discovered at the nexus of these two systems. We demonstrated that peroxisomes were required for immune cells to phagocytose of pathogens and drive antimicrobial signaling pathways and for the maintenance of enteric immunological homeostasis.
Our research program aims to define peroxisome-specific requirements during immune challenge. Much of peroxisome biology was explored in single cell systems, due to the severe early developmental interruptions caused by peroxisome defects in mice and humans. However, employing the vast genetic arsenal of the Drosophila model system allows us to finally explore the tissue-specific peroxisome contributions to immunity.
Going forward, we aim to understand the role that peroxisomes and peroxisome metabolic products (lipids and reactive species) play in the Drosophila Toll and IMD immune defense pathways (orthologous to the human Toll and TNF innate immune pathways) for the resolution of infection. Defining the roles of peroxisomes in these processes has implications for our understanding of peroxisome metabolic signaling in inflammation, immunodeficiency, cancer and diabetes and opens a new unexplored field of the innate immunity.
Defining How Macrophage Peroxisomes Contribute to Immune Functions.
We demonstrated that peroxisomes have a direct involvement in immune defense, with evidence that phagocytic clearance of pathogens by macrophages and other professional phagocytes is peroxisome-dependent.
Mapping peroxisome-dependent gene expression networks of the immune response in vivo.
Immune cell activation in response to infection involves a massive change in the gene expression profile. We found that immune cells lacking functional peroxisomes fail to activate key signaling pathways of the antimicrobial immune response during systemic infections. To better understand the global impact peroxisomes have on immune signaling pathways, we will map the peroxisome-dependent gene network during an infection.
The Peroxisome Role in Mucosal Immunity and Gut Health
In a recent study we found that peroxisomes in the Drosophila gut modulate the autophagy pathway, stress signaling and tissue regeneration to maintain gut epithelial homeostasis, promote gut epithelial renewal, and ultimately influence host–commensal and host–pathogen interactions needed for the survival and development. This demonstrated a key requirement of peroxisome functions in the gut epithelium for the organism health that was previously unknown. We now are investigating the molecular controls behind this requirement and how they impact immunity in human enteric tissues.
Francesca Di Cara
Dr. Francesca Di Cara joined the Departments of Pediatrics/Microbiology and Immunology as a new investigator at Dalhousie University in October 2018. Francesca received her PhD from the University of Naples “Federico II” at the Center for National Research, Naples, Italy. She then trained at the University of Edinburgh, Scotland under Dr. Margaret Heck before moving to the University of Alberta, Canada as a Postdoctoral Fellow with Dr. Kirst King-Jones, and then as a Research Associate under Drs. Andrew Simmonds and Richard Rachubinski.
Juyang joined the Di Cara in September to generate tissue-specific mutants in Drosophila, to investigated the role of peroxisomes in various immune responsive tissues.
Stephanie joined the Di Cara lab in September to study how peroxisomes regulate processes of phagocytosis.
Anu joined the lab in October and is, in addition to her technical work, supporting our work on peroxisome roles in phagocytosis.
Becca joined the Di Cara lab in October and is, in addition to her technical work supporting our research on immune roles for peroxisomes in mice.
The Dalhousie Medical Research Foundation provided funding for our startup funds research equipment needs.
Research Nova Scotia provides us funding support for our research program.
The Natural Sciences and Engineering Research Council provides support for our research on peroxisome roles in phagocytosis
The Canadian Institutes of Health Research provides funding support for our research on peroxisomes in immunometabolism.
The IWK Foundation provided establishment funds for our lab.
Canadian Foundation for Innovation provided funds for our research equipment through the CFI-JELF.
The Beatrice Hunter Cancer Research Institute provides funding support for Dania Shikara's summer research program.
Canada Research Chairs Suppports Dr. Di Cara, a Tier 2 Chair in Human Immunology and Host Pathogen Interactions.
New Frontiers Research Fund supports or research of how changes in the microbiome and diet affect neurodegenerative diseases.
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