Investigating immunodeficiency and infection responses in murine model of undernutrition

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Degree type
Doctor of Philosophy (PhD)
Graduate group
Cell and Molecular Biology
Discipline
Microbiology
Immunology and Infectious Disease
Biology
Subject
Immunodeficiency
Infection
Malnutrition
Nutrition
Refeeding
Undernutrition
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2023
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Author
Sukhina, Alisa
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Abstract

Undernutrition is a persistent global health crisis that heavily impacts both adults and children. The main underlying cause of morbidity and mortality from undernutrition is infectious disease. Although for over a century the link between poor infection outcomes and undernutrition has been reported, the cellular and molecular mechanisms of how chronic undernutrition causes immunodeficiency remains unknown. To investigate these mechanisms, we adapted a murine restrictive diet model to mimic physical characteristics of human undernutrition. We then performed comprehensive characterization of the immune system in these experimental mice before and after infection using flow cytometry. We found that both innate and adaptive immune responses were impaired in undernourished mice. Most myeloid cells, B cells, and T cells were all decreased in number before and after infection. Additionally, T cells exhibited delayed effector responses and diminished inflammatory cytokine production. But neutrophil numbers and their production levels during immune response to infection were decreased the most among all immune populations. After performing this characterization, we examined whether refeeding interventions, a standard of treatment for undernourished patients, can rescue immune cell numbers and function. We developed a safe refeeding protocol and performed the same analysis on refed mice. We found that most immune cell numbers and function have recovered, but neutrophils and their production levels stayed significantly lower in mice that used to be undernourished. These findings gave us insights into which arms of immune responses are most affected by undernutrition and the therapeutic potential of refeeding interventions on nutritionally acquired immunodeficiency. The findings of this study suggest that neutrophils are the population most negatively affected by undernutrition and that refeeding interventions have limitations in how effectively they can rescue immune responses. We hope that our work can both provide a solid foundation for future research into undernutrition-induced immunodeficiency and inform future standards of care and global policy focused on eradicating undernutrition.

Advisor
Bailis, Will
Date of degree
2023
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