Early immunity to Mycobacterium tuberculosis: new insights into macrophage heterogeneity and vaccine-mediated responses
type: CreativeWork
description: Tuberculosis (TB), caused by the bacteria Mycobacterium tuberculosis (Mtb), kills more individuals than any other single infectious agent. The only approved vaccine, BCG, poorly prevents the spread of disease, highlighting the fact that new vaccines are needed to eradicate TB. These efforts would benefit from a mechanistic understanding of how immunity to TB can be achieved as well as insight into the barriers that restrict immunity. However, a number of gaps in our knowledge of TB immunity remain. In particular, the interaction between Mtb and its target cell, the macrophage, during the early stages of infection remains incompletely understood. Here, we characterized the distinct response programs which are initiated in lung-resident alveolar macrophages (AM) and lung-infiltrating monocyte-derived macrophages (MDM). We find that infected AM harbor many more Mtb bacilli than infected MDM during both the innate and adaptive phases of the immune response. Using RNA-seq, we identified multiple differentially expressed pathways between the two cell types. While infected MDM upregulate canonical proinflammatory signaling pathways associated with Mtb control, infected AM are enriched for pathways relating to proliferation and fatty acid metabolism. Additionally, a number of genes relating to phagosome maturation and nitric oxide production were also differentially expressed. However, validation studies using gene knockout animals did not support a cell-intrinsic, protective role afforded by these genes. In addition to these host studies, we also investigated the transcriptional response of the Mtb itself. Here we found that Mtb in MDM have a transcriptional signature associated with late hypoxia, a known Mtb stress condition. We next used a mouse model of prior BCG immunization in order to understand how this vaccine alters early Mtb immunity. Here we found that BCG promotes a dramatic shift in the cell types targeted for Mtb infection. While AM are the major infected cel…
abstract: Tuberculosis (TB), caused by the bacteria Mycobacterium tuberculosis (Mtb), kills more individuals than any other single infectious agent. The only approved vaccine, BCG, poorly prevents the spread of disease, highlighting the fact that new vaccines are needed to eradicate TB. These efforts would benefit from a mechanistic understanding of how immunity to TB can be achieved as well as insight into the barriers that restrict immunity. However, a number of gaps in our knowledge of TB immunity remain. In particular, the interaction between Mtb and its target cell, the macrophage, during the early stages of infection remains incompletely understood. Here, we characterized the distinct response programs which are initiated in lung-resident alveolar macrophages (AM) and lung-infiltrating monocyte-derived macrophages (MDM). We find that infected AM harbor many more Mtb bacilli than infected MDM during both the innate and adaptive phases of the immune response. Using RNA-seq, we identified multiple differentially expressed pathways between the two cell types. While infected MDM upregulate canonical proinflammatory signaling pathways associated with Mtb control, infected AM are enriched for pathways relating to proliferation and fatty acid metabolism. Additionally, a number of genes relating to phagosome maturation and nitric oxide production were also differentially expressed. However, validation studies using gene knockout animals did not support a cell-intrinsic, protective role afforded by these genes. In addition to these host studies, we also investigated the transcriptional response of the Mtb itself. Here we found that Mtb in MDM have a transcriptional signature associated with late hypoxia, a known Mtb stress condition. We next used a mouse model of prior BCG immunization in order to understand how this vaccine alters early Mtb immunity. Here we found that BCG promotes a dramatic shift in the cell types targeted for Mtb infection. While AM are the major infected cel…
author: Delahaye, Jared L
language: en_US
keywords: Immunology
date published: 2019-10-15
date modified: 2026-07-24T05:58:20Z
provider: University of Washington
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Washington

PropertyValue
property ID: Handle
value: http://hdl.handle.net/1773/44833