Mycobacterium tuberculosis cords within lymphatic endothelial cells to evade host immunity

: The ability of Mycobacterium tuberculosis to form serpentine cords is intrinsically related to its virulence, but specifically how M. tuberculosis cording contributes to pathogenesis remains obscure. We show that several M. tuberculosis clinical isolates form intracellular cords in primary human lymphatic endothelial cells (hLEC) in vitro and also in the lymph nodes of patients with tuberculosis. We identified via RNA-seq a transcriptional programme that activates, in infected-hLECs, cell-survival and cytosolic surveillance of pathogens pathways. Consistent with this, cytosolic access is required for intracellular M. tuberculosis cording. Mycobacteria lacking ESX-1 type VII secretion system or PDIM expression, which fail to access to the cytosol, are indeed unable to cords within hLECs. Finally, we show that M. tuberculosis cording is a size-dependent mechanism used by the pathogen to avoid its recognition by cytosolic sensors and evade either resting or IFN-γ-induced hLEC immunity. These results explain the long-standing association between M. tuberculosis cording and virulence and how virulent mycobacteria use intracellular cording as strategy to successfully adapt and persist in the lymphatic tracts.