These data inform interventional strategies relevant to drug delivery, dosing, and diagnostics to prevent the development of acquired resistance. The role of high intracavitary penetration as a biomarker of antibiotic efficacy, when assessing new regimens, requires clarification.

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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-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.