Dissertation
Fleet-footed soldiers: circulating memory CD8 T cells quickly enter the fray during malarial and bacterial infection of the liver
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2023
DOI: 10.25820/etd.007176
Abstract
The highly vascularized liver may coordinate immune responses to infection or inflammation, and this non-lymphoid tissue is also a key target of clinically relevant pathogens. Chief among these pathogens is Plasmodium, the causative parasite of malaria, a disease that causes hundreds of thousands of deaths annually. The Plasmodium parasite must productively infect the liver before it can progress to potentially deadly blood-stage infection. Other pathogens that may target the liver include the bacteria Listeria monocytogenes and commensal microbes that escape from the gastrointestinal tract to cause sepsis. Antigen-specific memory CD8 T cells may exert control over infectious diseases by killing pathogen-infected host cells. The mechanisms by which memory CD8 T cells clear liver-localized pathogens, however, remain incompletely characterized. These knowledge gaps hinder scientists’ and physicians’ ability to develop novel treatments for infectious diseases of the liver. My thesis work, therefore, focused on determining if and how subsets of phenotypically and functionally distinct memory CD8 T cells control liver-stage malaria and other infections.
Using mouse models of liver-stage malaria, Listeria monocytogenes, and sepsis infections, I demonstrate that antigen-specific circulating effector memory CD8 T cells rapidly enter the malaria- or bacterially infected liver to exert control over the respective pathogen. This T cell recruitment relied on T-cell expressed LFA-1, liver phagocytes, and chemokine signaling. These findings highlighted the importance of considering circulating memory CD8 T cells when developing malaria vaccines. Also apparent in the data were unique differences between memory CD8 T cell recruitment to the liver as compared to other non-lymphoid tissues. These findings suggest that studying CD8 T cell biology in the context of liver infection may offer additional possibilities for combating human disease.
I next set out to apply my findings about circulating memory CD8 T cell protective capacity in a translational context. To this end, I developed a murine vaccine strategy for malaria that both more accurately recapitulated human responses to parasite vaccination and generated large numbers of resident and circulating memory CD8 T cells. A mouse-human weight-normalized radiation attenuated sporozoite (RAS) vaccination dose in mice induced partial non-sterilizing immunity to liver-stage malaria, which is similar to a human response to single RAS vaccination. Mice boosted with subunit vaccines based on recombinant attenuated bacterial or viral pathogens expressing liver-stage protective CD8 T cell epitopes increased both the number of memory CD8 T cells and conferred sterilizing immunity to the mice. This immunity was maintained even when the subunit vaccines were delivered intramuscularly, which is more clinically deliverable route than intravenous injection. My findings therefore inform human malaria vaccine development by demonstrating (1) that circulating memory CD8 T cells are a potentially important target during human vaccination efforts and (2) that a single RAS vaccination can be optimized by following it with more readily producible and deliverable subunit booster immunizations.
Details
- Title: Subtitle
- Fleet-footed soldiers: circulating memory CD8 T cells quickly enter the fray during malarial and bacterial infection of the liver
- Creators
- Mitchell Neill Lefebvre
- Contributors
- John T. Harty (Advisor)Noah S. Butler (Committee Member)Jon C. Houtman (Committee Member)Vladimir P. Badovinac (Committee Member)Ali Jabbari (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Biomedical Science (Immunology)
- Date degree season
- Spring 2023
- DOI
- 10.25820/etd.007176
- Publisher
- University of Iowa
- Number of pages
- xiv, 119 pages
- Copyright
- Copyright 2021 Mitchell Neill Lefebvre
- Language
- English
- Date submitted
- 03/21/2023
- Date approved
- 03/27/2023
- Description illustrations
- Illustrations, tables, graphs, charts
- Description bibliographic
- Includes bibliographical references (pages 112-119).
- Public Abstract (ETD)
Infectious diseases of the liver exert a profound annual toll on global public health. Chief among these is the mosquito-borne disease malaria, which causes hundreds of thousands of deaths each year. These deaths mostly occur in children residing in Sub-Saharan Africa. An effective, readily deliverable vaccine would considerably aid in antimalarial efforts; however, vaccine options remain limited despite decades of clinical trials.
Malaria must pass infect the human liver before it can cause blood-stage disease and potentially death. The liver-stage of malaria infection is therefore an appealing target for vaccination-induced immunity. Scientists do understand much about the immune responses necessary to fight off liver-stage malaria, however, there are many knowledge gaps about malaria that hinder effective vaccine development. To address these knowledge gaps, I studied how one branch of the immune system could be trained to fight liver-stage malaria more effectively.
My work determined that a type of immune cell called a “circulating memory CD8 T cell” can kill liver cells that are infected by the malaria parasite. This prevents the progression of blood-stage malaria. These long-lived memory CD8 T cells can be generated by certain kinds of vaccines. I leveraged these findings, along with other published data, to develop a mouse model of malaria vaccination that more accurately reflects vaccine responses in humans. Finally, the data generated by my thesis work may increase understanding of how to prevent and/or treat non-malarial infections of the liver because memory CD8 T cells may also control bacterial or viral liver infections.
- Academic Unit
- Biomedical Science Program
- Record Identifier
- 9984428942702771
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