Date of Award

2023-05-01

Degree Name

Doctor of Philosophy

Department

Biological Sciences

Advisor(s)

Charles T. Spencer

Abstract

Francisella tularensis (Ft.) is a gram-negative coccobacillus bacterium that causes the zoonotic disease tularemia in humans. Ft. causes the most severe, often fatal, form of the disease through inhalation. However, Ft. is most commonly transmitted through direct contact with infected animal carcasses such as rodents and rabbits, consumption of contaminated food or water, or through arthropod bites, particularly ticks. Due to its extremely low infectious dose, high mortality rate, and potential use as a biological warfare agent, Ft. is classified by the CDC as a "Tier 1 select agent". Ft. infection triggers an overactive inflammatory response, termed a "cytokine storm", which produces excessive tissue damage (and even failure) of vital organs, leading to rapid death of the host before its adaptive immunity responses can be brought to bear against the infection. In the periphery, macrophages, paradoxically the target cell for Ft., provide innate immune defense against foreign material, including bacteria. Microglia, the resident macrophage-like cells of the brain and spinal cord, rapidly respond to pathological changes in the central nervous system, serving a similar function as macrophages. Their rapid activation is an important factor in guarding the neural parenchyma against infectious diseases, inflammation, and neurodegeneration while maintaining and facilitating the return to tissue homeostasis. In the United States, several clinical cases of tularemia meningitis were diagnosed since 1931; however, there is no further research exploring the condition. We hypothesize that, after peripheral inoculation of Ft., the bacteria infiltrate the central nervous system using a Trojan horse-type mechanism and infect microglia, leading to overproduction of pro-inflammatory cytokines in the brain which then cause damage to surrounding neurons, ultimately leading to death. The research trajectory for this project is to: 1) identify the cellular targets of Ft. in the CNS; 2) identify the mechanism by which Ft. infiltrates the central nervous system; and 3) determine the resulting level of neuroinflammation in the brain after infection.

Language

en

Provenance

Recieved from ProQuest

File Size

p.

File Format

application/pdf

Rights Holder

Mireya Griselle Ramos-Muniz

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