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ORCID

http://orcid.org/0000-0002-6585-9655

Date of Award

Winter 1-15-2021

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Immunology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Mycobacterium tuberculosis (Mtb) is the leading cause of death by an infectious agent in the world today, infecting roughly one quarter of humans. Despite this, the mechanisms of early pathogenesis and host protective innate immune responses remain poorly understood and uncharacterized.

Lung resident Alveolar Macrophages (AMs) are the first host contact with Mtb bacilli after inhalation and are thus key mediators of the early pulmonary immune response. AMs are generally believed to reside entirely in the airway, but it was recently demonstrated that they have the capacity to egress and enter into granulomas during pulmonary infection with hypervirulent Mtb. Furthermore, we found that airway and non-airway AMs display distinct transcriptional profiles that suggest differential effector functions based on compartmental localization. The variety of effector function pathways expressed by non-airway AMs are primarily mediated by NF-kB signaling and are indicative of an M1 activation phenotype, which shifts the classic paradigm of AMs as permissive reservoirs for Mtb replication.

In the current work, we examine the host and Mtb factors/signals that modulate these compartmentally distinct AM effector functions and how these specific interactions determine protective or detrimental outcomes for the host. We examine the various functions that AMs contribute to the early immune response, focusing on migration from the airway, cellular interactions with epithelial or recruited immune cells, Mtb phagocytosis and killing, and inflammatory cytokine production. We also examine how specific Mtb cell wall lipid factors that mediate drug resistance and virulence can modulate these AM effector functions, thus skewing the host immune response.

Language

English (en)

Chair and Committee

Shabaana A. Khader

Committee Members

Gwendalyn J. Randolph, Marco Colonna, Andrew Kau, Michael Holtzman,

Available for download on Sunday, October 23, 2022

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