| Title: |
A blood-based transcriptional signature in a novel murine tuberculosis model predicts risk of human tuberculosis progression. |
| Authors: |
Plumlee, Courtney R; Gern, Benjamin H; Duffy, Fergal J; Delahaye, Jared; Rustad, Tige R; Aitchison, John D; Sherman, David R; Zak, Daniel E; Gerner, Michael Y; Urdahl, Kevin B |
| Source: |
The Journal of Immunology ; volume 200, issue Supplement_1, page 117.43-117.43 ; ISSN 0022-1767 1550-6606 |
| Publisher Information: |
Oxford University Press (OUP) |
| Publication Year: |
2018 |
| Description: |
Tuberculosis (TB) is a highly heterogeneous human disease that develops in a subset of individuals who inhale Mycobacterium tuberculosis (Mtb). Using advanced machine-learning algorithms, we discovered a blood transcriptional signature that identifies Mtb-exposed individuals in the process of progressing to active TB up to 18 months before they exhibit clinical symptoms. This signature may help prevent TB disease by identifying individuals who could benefit from early intervention. However, it fails to identify ~30% of progressors and does not reveal insights into the diverse outcome-governing pathways within the infected lung that underlie TB progression. To develop a tractable system that enables blood-based signatures to be linked to mechanistic pathways within the lung, we pioneered a novel murine TB model that recapitulates key aspects of human Mtb infection. We find that mice infected with a physiologic, ultra-low dose (i.e., 1–3 CFUs) of aerosolized Mtb exhibit a broad range of outcomes, with bacterial burdens ranging from less than 10 to ~106 CFUs within individual lungs. Mice that contain Mtb exhibit well-circumscribed granulomatous structures that share many features with human Mtb granulomas. In addition, we have identified a blood transcriptional signature that distinguishes "controller" and "progressor" mice. Remarkably, this mouse-derived signature is equally as effective as our previously identified human-derived signature at predicting TB risk in humans, confirming the model’s relevance to human disease. This finding enables us to use the tools of the tractable mouse system to address questions central to TB pathogenesis in a clinically relevant model. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.4049/jimmunol.200.supp.117.43 |
| Availability: |
https://doi.org/10.4049/jimmunol.200.supp.117.43; https://academic.oup.com/jimmunol/article/200/Supplement_1/117.43/7975190 |
| Rights: |
https://academic.oup.com/pages/standard-publication-reuse-rights |
| Accession Number: |
edsbas.1C296849 |
| Database: |
BASE |