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Spatial Network Mapping of Pulmonary Multidrug-Resistant Tuberculosis Cavities Using RNA Sequencing
- Source :
- American Journal of Respiratory and Critical Care Medicine
- Publication Year :
- 2019
- Publisher :
- AMER THORACIC SOC, 2019.
-
Abstract
- Rationale: There is poor understanding about protective immunity and the pathogenesis of cavitation in patients with tuberculosis. Objectives: To map pathophysiological pathways at anatomically distinct positions within the human tuberculosis cavity. Methods: Biopsies were obtained from eight predetermined locations within lung cavities of patients with multidrug-resistant tuberculosis undergoing therapeutic surgical resection (n = 14) and healthy lung tissue from control subjects without tuberculosis (n = 10). RNA sequencing, immunohistochemistry, and bacterial load determination were performed at each cavity position. Differentially expressed genes were normalized to control subjects without tuberculosis, and ontologically mapped to identify a spatially compartmentalized pathophysiological map of the cavity. In silico perturbation using a novel distance-dependent dynamical sink model was used to investigate interactions between immune networks and bacterial burden, and to integrate these identified pathways. Measurements and Main Results: The median (range) lung cavity volume on positron emission tomography/computed tomography scans was 50 cm3 (15–389 cm3). RNA sequence reads (31% splice variants) mapped to 19,049 annotated human genes. Multiple proinflammatory pathways were upregulated in the cavity wall, whereas a downregulation “sink” in the central caseum–fluid interface characterized 53% of pathways including neuroendocrine signaling, calcium signaling, triggering receptor expressed on myeloid cells-1, reactive oxygen and nitrogen species production, retinoic acid–mediated apoptosis, and RIG-I-like receptor signaling. The mathematical model demonstrated that neuroendocrine, protein kinase C-θ, and triggering receptor expressed on myeloid cells-1 pathways, and macrophage and neutrophil numbers, had the highest correlation with bacterial burden (r > 0.6), whereas T-helper effector systems did not. Conclusions: These data provide novel insights into host immunity to Mycobacterium tuberculosis–related cavitation. The pathways defined may serve as useful targets for the design of host-directed therapies, and transmission prevention interventions.
- Subjects :
- Adult
Male
Adolescent
Sequence Analysis, RNA
Mycobacterium tuberculosis
Original Articles
Middle Aged
Young Adult
transcriptomics
Case-Control Studies
Tuberculosis, Multidrug-Resistant
in silico analysis
TB cavitation
Humans
RNA, Viral
Female
Tuberculosis and Mycobacterial Disease
Tuberculosis, Pulmonary
pulmonary tuberculosis
Aged
Subjects
Details
- Language :
- English
- ISSN :
- 1073449X
- Database :
- OpenAIRE
- Journal :
- American Journal of Respiratory and Critical Care Medicine
- Accession number :
- edsair.pmid.dedup....f836e18e17da4c1c88557b461935d97b