Mycobacterium tuberculosis lipoprotein LprG binds lipoarabinomannan and determines its cell envelope localization to control phagolysosomal fusion.

Supriya Shukla,Niaz Banaei,W Henry Boom,Libin Shi,Clifford V Harding,Jaffre J Athman,Mary Jackson,Pamela A Wearsch,Edward T Richardson,David Mcdonald,David M Lewinsohn

doi:10.1371/journal.ppat.1004471

Abstract

Mycobacterium tuberculosis (Mtb) virulence is decreased by genetic deletion of the lipoprotein LprG, but the function of LprG remains unclear. We report that LprG expressed in Mtb binds to lipoglycans, such as lipoarabinomannan (LAM), that mediate Mtb immune evasion. Lipoglycan binding to LprG was dependent on both insertion of lipoglycan acyl chains into a hydrophobic pocket on LprG and a novel contribution of lipoglycan polysaccharide components outside of this pocket. An lprG null mutant (Mtb ΔlprG) had lower levels of surface-exposed LAM, revealing a novel role for LprG in determining the distribution of components in the Mtb cell envelope. Furthermore, this mutant failed to inhibit phagosome-lysosome fusion, an immune evasion strategy mediated by LAM. We propose that LprG binding to LAM facilitates its transfer from the plasma membrane into the cell envelope, increasing surface-exposed LAM, enhancing cell envelope integrity, allowing inhibition of phagosome-lysosome fusion and enhancing Mtb survival in macrophages.

Highlights

Tuberculosis is the second leading cause of death from an infectious disease worldwide
LprG functions as a carrier of lipoglycans in Mycobacterium tuberculosis (Mtb) These studies explored for the first time the lipoglycan/glycolipid binding function of the lipoprotein LprG expressed in Mtb
These lipoglycans/glycolipids were not associated with Mtb-expressed acylated LprA, a lipoprotein that is homologous to LprG; this control demonstrates the specificity of lipoglycan/glycolipid binding to LprG

Summary

Introduction

Tuberculosis is the second leading cause of death from an infectious disease worldwide (http://www.who.int/mediacentre/ factsheets/fs104/en/index.html). LAM is essential for Mtb survival; the synthesis of LAM and cell envelope arabinans is targeted by the anti-mycobacterial agent ethambutol and DprE1 inhibitors currently under development [12]. LAM inhibits Mtb phagosome-lysosome fusion, providing a mechanism for Mtb evasion of host defense [13,14,15,16,17,18]. This effect is specific to ManLAM, the mannose capped LAM found in slow growing strains that are pathogenic in humans or other host species (e.g. Mtb, M. bovis BCG, M. leprae), and is not produced by phospho-myoinositol-capped LAM (PI-LAM) found in M. smegmatis and M. fortuitum [13]. A model for Mtb cell envelope structure is presented by Kaur et al [1]

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Conclusion