Abstract
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.
Highlights
Mycobacterium tuberculosis (Mtb) infection leads to active tuberculosis (TB) in millions of people annually (Kaufmann et al, 2018)
Given the lung is a main port of entry for Mtb and the primary organ of pulmonary TB (Kaufmann et al, 2014), we interrogated whether AG affects the lung by employing the chemically synthesized AG composed of 92 mono-saccharide units (Wu et al, 2017)
To further verify the function of AG, we performed an in vitro selection process called Systematic Evolution of Ligands by Exponential Enrichment (SELEX) of aptamers (Tuerk & Gold, 1990; Bock et al, 1992) against AG (Appendix Fig S2A), which has been successfully applied for the screening of aptamers targeting Mtb previously (Qin et al, 2014; Aimaiti et al, 2015; Sun et al, 2016; Tang et al, 2016; Zhang et al, 2017; Golichenari et al, 2018)
Summary
Mycobacterium tuberculosis (Mtb) infection leads to active tuberculosis (TB) in millions of people annually (Kaufmann et al, 2018). In 2019, 10 million new TB cases and 1.4 million deaths were reported (WHO Global Tuberculosis Report, 2020). An estimated quarter of the world’s population is infected with Mtb, but only 5–10% of infected individuals succumb to active TB disease (WHO Global Tuberculosis Report, 2020). The pathogenesis of TB is shaped by an intricate balance between host immunity and Mtb infection (Orme et al, 2015). Mtb has developed numerous strategies to evade or inhibit host innate immunity (Hmama et al, 2015; Liu et al, 2017a; Chai et al, 2020)
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