title: Lymphatic endothelial cells are a replicative niche for Mycobacterium tuberculosis.
abstract: In extrapulmonary tuberculosis, the most 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-γ 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.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Lerner
authors.forename: Cristiane
authors.initials: C
authors.lastname: de Souza Carvalho-Wodarz
authors.forename: Urska
authors.initials: U
authors.lastname: Repnik
authors.forename: Matthew R G
authors.initials: MR
authors.lastname: Russell
authors.forename: Sophie
authors.initials: S
authors.lastname: Borel
authors.forename: Collin R
authors.initials: CR
authors.lastname: Diedrich
authors.forename: Manfred
authors.initials: M
authors.lastname: Rohde
authors.forename: Helen
authors.initials: H
authors.lastname: Wainwright
authors.forename: Lucy M
authors.initials: LM
authors.lastname: Collinson
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Wilkinson
authors.forename: Gareth
authors.initials: G
authors.lastname: Griffiths
authors.forename: Maximiliano G
authors.initials: MG
authors.lastname: Gutierrez
mesh_terms: D001343:Autophagy; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000382:microbiology*; D006099:Granuloma / Q000382:microbiology; D006801:Humans; D008198:Lymph Nodes / Q000382:microbiology / Q000473:pathology; D009169:Mycobacterium tuberculosis / Q000254:growth & development*; D009569:Nitric Oxide / Q000096:biosynthesis; D014376:Tuberculosis / Q000276:immunology / Q000382:microbiology*
chemical_list: D009569:Nitric Oxide