Semester

Spring

Date of Graduation

2023

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Microbiology, Immunology, and Cell Biology

Committee Chair

Cory Robinson

Committee Member

Mariette Barbier

Committee Member

Christopher Cuff

Committee Member

Jennifer Franko

Committee Member

Werner Geldenhuys

Abstract

Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis (TB), a predominantly respiratory pathogen responsible for over ten million infections and one million deaths last year. Despite it being a primary objective of the World Health Organization (WHO) for several decades to irradicate TB, progress toward this objective has fallen short of the 2020 target to end TB by 2035. Meeting this goal will require advancements in diagnostic tools, education, healthcare access, and treatments and preventatives. Regarding prevention, the primary tool for this strategy is through vaccination. Currently, the only licensed vaccine for protection against TB is the century old bacillus Calmette Guérin (BCG). BCG is predominantly used where TB is endemic, where it is ideally given as near after birth as possible to offer protection. While this vaccine does protect young children against TB and its disseminated forms, its efficacy in older populations is highly variable, suggesting a poor ability to produce long-term immunity. Improving BCG or altogether developing a new, more protective vaccine is thus a logical route to controlling the TB epidemic. Unfortunately, no vaccine candidate to date has been successful. In the present dissertation, we proposed this failure arises from an incomplete appreciation for the unique immune environment of the neonate. Neonatal immunity is distinct from that of older age groups, be it in mice or humans. Therefore, studying vaccine responses in an age-appropriate model of vaccination could provide better representations of protection following immunization. To explore this, we developed a neonatal mouse model of vaccination and in vitro assessment. Following previous observations from our lab, we were interested in the influence of the cytokine interleukin (IL)-27. This cytokine is immunosuppressive and we have previously shown it is elevated in the neonatal period when children are being immunized with BCG. Here, we explored the role of IL-27 in the neonatal period following BCG vaccination using our neonatal mouse models of BCG administration and a mouse unresponsive to IL-27 as a result of deletion in its receptor (IL-27Rα-KO). We observed improved production of IL-12 from neonatal dendritic cells with greater stimulation of CD4+ T cells in the absence of IL-27. Furthermore, we showed where clearance of BCG in vitro and in vivo is improved in the absence of IL-27 signaling. Finally, we observed improved control of Mtb in our IL-27Rα-KO alongside a shift to increased production of inflammatory cytokines in the lungs. We conclude that the studies herein offer substantial support for the important negative contributions of IL-27 during neonatal vaccination and suggest that greater consideration be taken to the unique immune environment during early-life vaccination and the development of vaccines for this age group to better model anticipated responses.

Embargo Reason

Publication Pending

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