Lipoarabinomannan and related glycoconjugates: structure, biogenesis and role inMycobacterium tuberculosisphysiology and host–pathogen interaction

Arun K Mishra,Ben J Appelmelk,Gurdyal S Besra,Nicole N Driessen

doi:10.1111/j.1574-6976.2011.00276.x

Arun K Mishra, Ben J Appelmelk + Show 2 more

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https://doi.org/10.1111/j.1574-6976.2011.00276.x

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Abstract

Approximately one third of the world's population is infected with Mycobacterium tuberculosis, the causative agent of tuberculosis. This bacterium has an unusual lipid-rich cell wall containing a vast repertoire of antigens, providing a hydrophobic impermeable barrier against chemical drugs, thus representing an attractive target for vaccine and drug development. Apart from the mycolyl–arabinogalactan–peptidoglycan complex, mycobacteria possess several immunomodulatory constituents, notably lipomannan and lipoarabinomannan. The availability of whole-genome sequences of M. tuberculosis and related bacilli over the past decade has led to the identification and functional characterization of various enzymes and the potential drug targets involved in the biosynthesis of these glycoconjugates. Both lipomannan and lipoarabinomannan possess highly variable chemical structures, which interact with different receptors of the immune system during host–pathogen interactions, such as Toll-like receptors-2 and C-type lectins. Recently, the availability of mutants defective in the synthesis of these glycoconjugates in mycobacteria and the closely related bacterium, Corynebacterium glutamicum, has paved the way for host–pathogen interaction studies, as well as, providing attenuated strains of mycobacteria for the development of new vaccine candidates. This review provides a comprehensive account of the structure, biosynthesis and immunomodulatory properties of these important glycoconjugates.

Highlights

The biosynthetic machinery of the mycobacterial cell wall, which is the site of action of many front-line tuberculosis drugs, represents an attractive drug target (Bhatt et al, 2007; Bhowruth et al, 2007; Brennan & Crick, 2007; Dover et al, 2008)
We review the localization and trafficking of these immunomodulatory lipoglycans and discuss recent findings concerning the role of CD1, TLR, dendritic cells (DCs)-SIGN and macrophage mannose receptor (MMR) in M. tuberculosis infection
It was suggested that MptA and MptC may act in close coordination to synthesize mature lipomannan and lipoarabinomannan, and the length of the mannan core may be regulated by a branching-dependent chain termination mechanism (Sena et al, 2010)

Summary

Introduction

FEMS Microbiol Rev 35 (2011) 1126–1157Structure, function and biogenesis of lipoarabinomannan receptors (TLR) signaling, the higher-order PIMs and mannose-capped lipoarabinomannan (Man-LAM) are recognized by the C-type lectins, such as dendritic cell-specific intercellular adhesion molecule-3 (ICAM-3) grabbing nonintegrin (DC-SIGN) and the macrophage mannose receptor (MMR) (Schlesinger et al, 1994; Chatterjee & Khoo, 1998; Nigou et al, 2002; Geijtenbeek et al, 2003; Maeda et al, 2003).Because of the advent of MDR and XDR strains of M. tuberculosis (Sreevatsan et al, 1997; Telenti et al, 1997; Heymann et al, 1998; Chan & Iseman, 2008; Wright et al, 2009), there is an urgent need to identify novel drug targets and the development of active compounds. It was suggested that the 6-OH position of the O-2 mannose attached to the inositol of PIM2 is substituted by a C16 fatty acyl-substituent, which is present in lipomannan and lipoarabinomannan from M. tuberculosis and Mycobacterium leprae (Khoo et al, 1995a).

Results

Conclusion