CD147 Hooks Meningococcus

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Science Translational Medicine  25 Jun 2014:
Vol. 6, Issue 242, pp. 242ec111
DOI: 10.1126/scitranslmed.3009600

Neisseria meningitidis, or meningococcus, is a Gram-negative bacterium and part of the normal nasopharyngeal microbiota. This microorganism becomes dangerous when meningococci reach the circulation and spread to various tissues, causing meningitis or purpura fulminans (a severe invasive form of the disease). Despite antimicrobial therapy, systemic meningococcal infections remain a major cause of mortality and severe neurological sequelae.

Targeting the endothelium that lines blood and lymphatic vessels is a crucial step in the pathogenesis of invasive bloodborne meningococci. This event leads to vascular colonization that is characterized by microbial adhesion and proliferation in both peripheral and brain blood microvessels. Type IV pili mediate adhesion to endothelial cells, allowing bacterial translocation through the endothelium. However, the host-derived ligands for these pili and their consequences in the pathogenesis of N. meningitidis have not been previously identified.

Bernard et al. sought to investigate the ligands for different meningococcal pili and their role in the establishment of bacterial infection in human cells and tissues. Activating a human brain endothelial cell line with 12-O-tetradecanoylphorbol 13-acetate (TPA) (a potent transcriptional regulator) increased the adhesion of N. meningitidis. When the authors performed a differential, quantitative, large-scale analysis of gene expression, they found that expression of CD147 (a member of the immunoglobulin superfamily and a marker of brain capillaries) was greatly enhanced when compared with unstimulated cells and that CD147 accumulated at sites of meningococcal adhesion to two different types of human endothelial cells. The authors used multiple approaches to inhibit CD147 expression and function and determined that CD147 was required to mediate Neisseria adhesion. In addition, they identified PilE and PilV as CD147 ligands and showed that deletion of these two components of pili prevented colonization of vessels in human brain tissue explants ex vivo and in humanized mice in vivo.

Together, these findings demonstrate the molecular basis of a key pathophysiological step in human meningococcal disease and identify a role for CD147 in the cascade of events that follow meningococcal entry into the bloodstream. Therapeutic approaches that focus on preventing type IV pilus interaction with CD147 might be effective for treatment or prevention of meningococcal infection and associated vascular dysfunction.

S.C. Bernard et al., Pathogenic Neisseria meningitidis utilizes CD147 for vascular colonization. Nat. Med. 10.1038/nm.3563 (2014). [Full Text]

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