Journal
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
Volume 200, Issue 3, Pages 370-380Publisher
AMER THORACIC SOC
DOI: 10.1164/rccm.201807-1361OC
Keywords
transcriptomics; pulmonary tuberculosis; in silico analysis; TB cavitation
Categories
Funding
- Baylor Research Institute
- NIH [DP2 OD001886, R01AI079497, R56 AI111985]
- South African MRC
- European Developing Clinical Trials Partnership
- National Research Foundation
- Oppenheimer Foundation
- Wellcome Trust [207511/Z/17/Z, WT101766/Z/13/Z]
- Medical Research Council [MR/M003833/1]
- NIHR Biomedical Research Funding
- MRC [MR/M003833/1] Funding Source: UKRI
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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 cm(3) (15-389 cm(3)). 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-theta, 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.
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