Diversity in Mycobacterium tuberculosis mannosylated cell wall determinants impacts adaptation to the host

Abstract

Summary Mycobacterium tuberculosis (the causal agent of TB) has co-evolved with humans for centuries. It infects via the airborne route and is a prototypic highly adapted intracellular pathogen of macrophages. Extensive sequencing of the M. tuberculosis genome along with recent molecular phylogenetic studies is enabling us to gain insight into the biologic diversity that exists among bacterial strains that impact the pathogenesis of latent infection and disease. The majority of the M. tuberculosis cell envelope is comprised of carbohydrates and lipids, and there is increasing evidence that these microbial determinants that are readily exposed to the host immune system play critical roles in disease pathogenesis. Studies from our laboratory and others have raised the possibility that M. tuberculosis is adapting to the human host by cloaking its cell envelope molecules with terminal mannosylated (i.e. Man-α-(1→2)-Man) oligosaccharides that resemble the glycoforms of mammalian mannoproteins. These mannosylated biomolecules engage the mannose receptor (MR) on macrophages during phagocytosis and dictate the intracellular fate of M. tuberculosis by regulating formation of the unique vesicular compartment in which the bacterium survives. The MR is highly expressed on alveolar macrophages (predominant C-type lectin on human cells) and functions as a scavenger receptor to maintain the healthiness of the lung by clearing foreign particles and at the same time regulating dangerous inflammatory responses. Thus M. tuberculosis exploits MR functions to gain entry into the macrophage and survive. Key biochemical pathways and mycobacterial determinants involved in the development and maintenance of the M. tuberculosis phagosome are being identified. The phylogenetic diversity observed in M. tuberculosis strains that impact its cell wall structure together with the genetic diversity observed in human populations, including those elements that affect macrophage function, may help to explain the extraordinary evolutionary adaptation of this pathogen to the human host. Major developments in these areas are the focus of this review.

Mycobacterium tuberculosislipomannan blocks TNF biosynthesis by regulating macrophage MAPK-activated protein kinase 2 (MK2) and microRNA miR-125b

“…Whereas much attention has been given to the biological properties of mannose-capped lipoarabinomannan and PIMs, there has been less interest in studying LM. Mycobacterial LM is structurally defined by a GPI anchor linked to a linear α(1→6)-mannan containing some α(1→2)-mannose branches (2). In particular, LMs from different mycobacterial species exhibit both proinflammatory and anti-inflammatory responses through Toll-like receptor (TLR) 2-dependent and -independent pathways (3,4).…”

Structural Differences in Lipomannans from Pathogenic and Nonpathogenic Mycobacteria That Impact CD1b-restricted T Cell Responses

“…Overall, LM molecules have been shown to regulate cytokine, oxidant, and T cell responses (1). LM populations from M. tuberculosis H 37 R v associate with DC-SIGN but not with the MR and induce apoptosis and IL-12 production (1).…”

“…S1. 1 number of fatty acids per molecule (1). To what extent structural differences in a particular LM molecule dictate its immune effects is still unknown.…”

Optimization of inhaled therapies for tuberculosis: The role of macrophages and dendritic cells

“…[4], [75], [76], [77], [78] and [79] Bloom's group in 199180 reported a potential role for lipoarabinomannans [LAM] as factors in the persistence of M. tuberculosis in infected cells, and other studies also attributed this capacity specifically to manLAM. [81] and [82] Most recently, Schlesinger and Torrelles have demonstrated that M. tuberculosis clinical isolates vary in their degree of surface mannosylation and they suggest these differences may have great impact on the outcome of the disease.78 There is direct evidence manLAM affects DC maturation and function [79], [83] and [84] and the same antigen either as a cell wall component of M. tuberculosis or as a free antigen, drives DCs into IL-10 production.…”