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Cell-Type Specific Immune Profiles Inform Tuberculosis Disease Severity and Protective Efficacy Outcomes of an Attenuated Mycobacterium tuberculosis Vaccine Candidate

Year: 2026
Type: dissertation
Abstract: Mycobacterium tuberculosis (Mtb) is the cause of tuberculosis (TB), an ancient disease that remains a significant global health problem. Reducing the global incidence and death rates of TB is a top priority of the World Health Organization and the Bill & Melinda Gates Foundation. The current preventive strategy, vaccination of infants with Bacille Calmette-Guérin (BCG), a live attenuated strain of Mycobacterium bovis, is widely used around the world. However, BCG only provides immunity until ~15 years of age and has severe limitations in adult populations. Over the past 10 years there has been accelerated progress in designing and testing new vaccine strategies; however, to achieve the goal of ending the TB epidemic many hurdles remain to be overcome. In this work I have progressed our knowledge on correlates of TB disease severity in mice using high-dimensional proteomic immune profiling, flow cytometry, and in situ hybridization. I also validated an Mtb strain with a deletion of the nucleoid associated protein Lsr2 (Δlsr2) as a promising live attenuated vaccine candidate. I found that CD39 expression across multiple cell-types, particularly T cells, to be a strong marker of TB disease severity. I also found that vaccination with Δlsr2 induces robust IFNγ and TNF expression in CD4 and CD8 T cells in mice and affords enhanced protection against Mtb in both mice and guinea pigs. Lastly, I performed an exploratory, large-scale, long-term immune profiling of multiple Mtb immunity conditions in male and female mice and found a considerable vaccine-strategy-dependent sex bias in both TB severity and immune response during late infection. Altogether, this work shows the power of broader, unbiased immune modeling to make meaningful discoveries in the mouse model towards new methods of tuberculosis prevention and control.
Language: English
Field: Medicine
Open Access status: green
OpenAlex ID: W7204015326
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