Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 126, Issue 3, Pages 1093-1108Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI83379
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Funding
- Coordination for the Improvement of Higher Education [0561-11-8]
- Helmholtz Young Investigator grant [VH-NG-527]
- Francis Crick Institute from Cancer Research UK
- UK Medical Research Council [MC_UP_1202/11, U1175.02.002.00014]
- Wellcome Trust [104803, 084323]
- Claude Leon Foundation
- European Commission [FP7-PEOPLE-2011-IRSES]
- German Research Council (DFG) [SPP1580]
- Medical Research Council [MC_UP_1202/11] Funding Source: researchfish
- The Francis Crick Institute [10219, 10092, 10004, 10218] Funding Source: researchfish
- Wellcome Trust [104803/Z/14/Z] Funding Source: researchfish
- MRC [MC_UP_1202/11] Funding Source: UKRI
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In extrapulmonary tuberculosis, the mast common site of infection is within the lymphatic system, and there is growing recognition that lymphatic endothelial cells (LECs) are involved in immune function. Here, we identified LECs, which line the lymphatic vessels, as a niche for Mycobacterium tuberculosis in the lymph nodes of patients with tuberculosis. In cultured primary human LECs (hLECs), we determined that M. tuberculosis replicates both in the cytosol and within autophagosomes, but the bacteria failed to replicate when the virulence locus RD1 was deleted. Activation by IFN-gamma induced a cell-autonomous response in hLECs via autophagy and NO production that restricted M. tuberculosis growth. Thus, depending on the activation status of LECs, autophagy can both promote and restrict replication. Together, these findings reveal a previously unrecognized role for hLECs and autophagy in tuberculosis pathogenesis and suggest that hLECs are a potential niche for M. tuberculosis that allows establishment of persistent infection in lymph nodes.
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