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Date of Award
Doctor of Philosophy (PhD)
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is the number one killer due to a single infectious agent. Although, there is a vaccine against TB and antimicrobial treatments available, approximately 1.8 million people die each year. This underlines the importance of identifying and understanding mediators of TB pathogenesis to develop new diagnostics for early detection and therapies to treat individuals progressing to active disease. One of the cellular mediators that may play a role in TB pathogenesis are neutrophils. Neutrophils have been associated with active Tuberculosis (ATB); however, the role that neutrophils play within Mtb infection and disease is still unknown. To further understand the role that neutrophils play within TB pathogenesis, neutrophils were depleted in the acute and chronic stages of infection. Neutrophil depletion did not impact susceptibility during acute stages; however, susceptibility was significantly decreased during chronic stages. This suggests neutrophils promote Mtb infection and pathogenesis during the chronic stage of infection. This body of work demonstrates that decreasing neutrophil accumulation in the lung and promoting host protection can be mediated through neutrophil proteins, such as S100A8/A9, as well as TGF-β, an anti-inflammatory cytokine. Results demonstrate that S100A8/A9 promotes chronic increases susceptibility and may be mediated through CD11b dependent lung neutrophil accumulation and Mtb uptake. While not a neutrophilic protein, TGF-β inhibition significantly decreases susceptibility and neutrophil accumulation as chronic disease progressed. Overall, these results provide evidence that S100A8/A9 and TGF-β contribute to neutrophil mediated accumulation and Mtb infection and pathogenesis.
Chair and Committee
Shabaana A. Khader
Michael Holtzman, Daniel Link, Mary Dinauer, Deborah Lenschow,
Scott, Ninecia, "Elucidation of the role of S100A8/A9 and neutrophils in chronic tuberculosis" (2019). Arts & Sciences Electronic Theses and Dissertations. 1948.
Available for download on Saturday, August 29, 2020