Electronic Thesis and Dissertation Repository

Thesis Format

Monograph

Degree

Master of Science

Program

Microbiology and Immunology

Supervisor

Leligdowicz, Aleksandra

2nd Supervisor

Heit, Bryan

Co-Supervisor

Abstract

Critical illness, a state of health instability and organ dysfunction necessitating urgent medical attention, is often characterized by dysregulated immune responses, which can counterintuitively lead to immunosuppression. As such, critically ill patients are at high risk of secondary infections and a prolonged unstable health status. Monocyte-derived macrophages (MDMs) are tissue-resident innate immune cells originating from circulating monocytes. MDMs play a crucial role in orchestrating immune responses in critical illnesses and can differentiate into an inflammatory (M1) or anti-inflammatory (M2) state dictated by the tissue status where they migrate. MDMs are responsible for maintaining tissue homeostasis by performing phagocytosis and pathogen clearance, functions that are dependent on their inflammatory state. In this study, I investigated the phagocytosis and bacteria-killing function of MDMs derived from the peripheral blood of healthy donors and critically ill patients. Moreover, I aimed to understand alterations in the functionality of these MDMs following lipopolysaccharide (LPS) treatment in both health and critical illness. This study revealed that LPS treatment causes decreased phagocytosis and bacteria killing in health and critical illness, indicating an induced tolerance in most critically ill patients. Moreover, LPS re-stimulated inflammatory (M1) MDMs demonstrated a reduction in the phagocytosis index of most critically ill patients. The findings suggest that most MDM responses are similar in health and critical illness, with reduced MDMs’ responses after LPS restimulation demonstrating an induced immune tolerance in health and critical illness.

Summary for Lay Audience

Critically ill patients are individuals who require urgent medical attention in the intensive care unit (ICU). In critical illness, unbalanced health status and uncontrolled immune responses lead to lower immune function, which can eventually result in organ dysfunction and death. This status makes the body less responsive to infections rather than successfully fighting them. As a result, critically ill patients are more likely to experience secondary infections, ongoing health problems, and prolonged ICU stays. My research focuses on a specific type of immune cells called monocyte-derived macrophages (MDMs). These cells originate from monocytes, a type of white blood cell circulating in the bloodstream. MDMs play a crucial role in the immune system, especially in fighting infections and maintaining the health of body tissues. MDMs are long-lived cells that are highly adaptable as they can shift to either a pro-inflammatory or anti-inflammatory state depending on the status of the tissue where they migrate. Their ability to engulf and kill harmful bacteria is vital for keeping the body free of infections. In this thesis, I examined the function of MDMs, particularly in their ability to engulf, or phagocytose, and kill bacteria in healthy individuals and critically ill patients. I also examined how these cells respond to treatment with a bacterial component called lipopolysaccharide (LPS), a substance that mimics bacterial infection. These findings revealed that, in critically ill patients, LPS treatment of MDMs causes tolerance or suppression in the cells’ ability to engulf and kill bacteria, especially in the cells derived from critically ill patients. These insights are essential for understanding MDM immune responses in health and critical illness and may lead to the development of new treatments that can improve the health of critically ill patients in the ICU.

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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