Mycobacterium tuberculosis cords within lymphatic endothelial cells to evade host immunity

Area of Science:

• Microbiology
• Immunology
• Pathogenesis

Background:

• The virulence of Mycobacterium tuberculosis is linked to its ability to form serpentine cords.
• The precise role of M. tuberculosis cording in disease pathogenesis is not well understood.

Purpose of the Study:

• To investigate the formation of intracellular cords by M. tuberculosis in human lymphatic endothelial cells (hLECs).
• To elucidate the mechanisms by which M. tuberculosis cording contributes to virulence and immune evasion.

Main Methods:

• RNA-sequencing (RNA-Seq) to identify transcriptional programs in infected hLECs.
• Analysis of M. tuberculosis mutants lacking specific virulence factors (ESX-1 secretion system, phthiocerol dimycocerosates).
• In vitro studies using primary hLECs and in vivo examination of lymph nodes from tuberculosis patients.

Main Results:

• M. tuberculosis clinical isolates form intracellular cords within hLECs and in patient lymph nodes.
• Infected hLECs activate cell survival and cytosolic pathogen surveillance pathways.
• Cytosolic access is essential for intracellular cord formation; mutants lacking ESX-1 or phthiocerol dimycocerosates cannot form cords.
• Cording is a size-dependent mechanism for evading cytosolic sensors and hLEC immunity.

Conclusions:

• M. tuberculosis utilizes intracellular cording to evade host immunity, particularly within lymphatic endothelial cells.
• This cording strategy is crucial for the pathogen's adaptation, persistence, and virulence in lymphatic tracts.
• The findings explain the correlation between M. tuberculosis cording and disease severity.