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Lymphatic endothelial cells are a replicative niche for Mycobacterium tuberculosis
Thomas R. Lerner, … , Gareth Griffiths, Maximiliano G. Gutierrez
Thomas R. Lerner, … , Gareth Griffiths, Maximiliano G. Gutierrez
Published February 22, 2016
Citation Information: J Clin Invest. 2016;126(3):1093-1108. https://doi.org/10.1172/JCI83379.
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Research Article Cell biology Infectious disease Article has an altmetric score of 7

Lymphatic endothelial cells are a replicative niche for Mycobacterium tuberculosis

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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

Thomas R. Lerner, Cristiane de Souza Carvalho-Wodarz, Urska Repnik, Matthew R.G. Russell, Sophie Borel, Collin R. Diedrich, Manfred Rohde, Helen Wainwright, Lucy M. Collinson, Robert J. Wilkinson, Gareth Griffiths, Maximiliano G. Gutierrez

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Figure 7

Proposed model of M. tuberculosis dynamics in infected hLECs.

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Proposed model of M. tuberculosis dynamics in infected hLECs.
M. tubercu...
M. tuberculosis (green) are phagocytosed by hLECs and initially reside in the phagosome (brown). At 24 hours after infection, 70% to 90% of the bacteria escape into the cytosol, but this is strictly RD1 dependent. M. tuberculosis lacking RD1 and a small fraction of RD1+ M. tuberculosis are trafficked directly to phagolysosomes (P-L) and suffer restricted growth/killing (this process is also induced by IFN-γ). In the cytosol, M. tuberculosis can readily replicate, but this is restricted when IFN-γ is present via the relocalization of intracellular eNOS to generate NO in the immediate vicinity of the bacteria. A small population of M. tuberculosis also enters the autophagy pathway in an RD1-dependent manner, directly from the phagosome and/or via the cytosol. M. tuberculosis induces autophagosome formation and can replicate in an LC3+ compartment by blocking fusion of lysosomes with the autophagosome. Upon activation of hLECs by IFN-γ, autophagosome-lysosome fusion is restored (i.e., increased autophagic flux), and M. tuberculosis growth is restricted in autophagolysosomes (A-L).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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