Sensing of mycobacterial arabinogalactan by galectin-9 exacerbates mycobacterial infection

Mycobacterial arabinogalactan (AG) is an essential cell wall component of mycobacteria and a frequent structural and bio-synthetical target for anti-tuberculosis (TB) drug development. Here, we report that mycobacterial AG is recognized by galectin-9 and exacerbates mycobacterial infection. Administration of AG-specific aptamers inhibits cellular infiltration caused by Mycobacterium tuberculosis ( Mtb ) or Mycobacterium bovis BCG, and moderately increases survival of Mtb -infected mice or Mycobacterium marinum- infected zebrafish. AG interacts with carbohydrate recognition domain (CRD) 2 of galectin-9 with high affinity, and galectin-9 associates with transforming growth factor β-activated kinase 1 (TAK1) via CRD2 to trigger subsequent activation of extracellular signal-regulated kinase (ERK) as well as induction of the expression of matrix metalloproteinases (MMPs). Moreover, deletion of galectin-9 or inhibition of MMPs blocks AG-induced pathological impairments in the lung, and the AG-galectin-9 axis aggravates the process of Mtb infection in mice. These results demonstrate that AG is an important virulence factor of mycobacteria and galectin-9 is a novel receptor for Mtb and other mycobacteria, paving the way for the development of novel effective TB immune modulators. SYNOPSIS Arabinogalactan is a virulence factor of mycobacteria. Binding of galectin-9 to mycobacterial arabinogalactan triggers matrix metalloproteinases via TAK1-ERK signaling, which promotes mycobacterial infection and increases lung injury. Arabinogalactan exacerbates mycobacterial infection by causing lung injury. AG-specific aptamers inhibit cellular mycobacterium infiltration and increase survival of infected mice or fish. Galectin-9 is a receptor for mycobacterial arabinogalactan and activates the TAK1- ERK-MMP signaling axis. The Arabinogalactan-galectin-9 interface may be exploited for the design of new host-directed therapies. Graphical Abstract Arabinogalactan is a virulence factor of mycobacteria. Binding of galectin-9 to mycobacterial arabinogalactan triggers matrix metalloproteinases via TAK1-ERK signaling, which promotes mycobacterial infection and increases lung injury.