A glycolipid of hypervirulent tuberculosis strains that inhibits the innate immune response

Abstract

Fifty million new infections with Mycobacterium tuberculosis occur annually, claiming 2-3 million lives from tuberculosis worldwide. Despite the apparent lack of significant genetic heterogeneity between strains of M. tuberculosis, there is mounting evidence that considerable heterogeneity exists in molecules important in disease pathogenesis. These differences may manifest in the ability of some isolates to modify the host cellular immune response, thereby contributing to the observed diversity of clinical outcomes. Here we describe the identification and functional relevance of a highly biologically active lipid species-a polyketide synthase-derived phenolic glycolipid (PGL) produced by a subset of M. tuberculosis isolates belonging to the W-Beijing family that show 'hyperlethality' in murine disease models. Disruption of PGL synthesis results in loss of this hypervirulent phenotype without significantly affecting bacterial load during disease. Loss of PGL was found to correlate with an increase in the release of the pro-inflammatory cytokines tumour-necrosis factor-alpha and interleukins 6 and 12 in vitro. Furthermore, the overproduction of PGL by M. tuberculosis or the addition of purified PGL to monocyte-derived macrophages was found to inhibit the release of these pro-inflammatory mediators in a dose-dependent manner.

Broadening Our View About the Role of Mycobacterium tuberculosis Cell Envelope Components During Infection: A Battle for Survival

“…As a consequence, mycobacteria develop aqueous channels formed by porin molecules in the cell wall structure. Other distinguishing cell wall components of M.tb include ManLAM, LM, PIMs, and a peripheral layer of lipids such as trehalose mycolates (trehalose dimycolate or TDM, trehalose monomycolate or TMM), lipooligosaccharides (LOSs), phenolic glycolipids [PGLs, described in some M.tb clinical isolates (Reed et al, 2004;Torrelles et al, 2008b)], acyl trehaloses (diacylor DAT and triacyl-or TAT), triglycerides and sulfolipids (SLs) (Brennan & Nikaido, 1995;Muñoz et al, 1997aMuñoz et al, , 1997b. Recently, the role for individual components of the cell wall has been elucidated, and much emphasis has been placed on the identification and characterization of various genes that encode enzymes involved in the synthesis of the cell wall constituents.…”

“…Recently, the hypervirulent phenotype observed in several strains of M.tb (i.e. strain HN878) has been associated with the presence of PGL in their cell wall (Reed et al, 2004).…”

“…Why do clinical isolates of M.tb present different cell wall rearrangements than the widely studied M.tb laboratory strains Erdman, H 37 R v , and H 37 R a ? In this context, hypervirulent M.tb strains of the Beijing family (Tsenova et al, 2005) are shown to contain large amounts of triglycerides (Reed et al, 2007), and some of them also contain the PGL-TB (Reed et al, 2004). M.tb clinical isolates deficient in ManLAM and PIMs surface exposure, but presenting in their cell wall large quantities of triglycerides, PGL-TB, and dimycocerosates, are also shown to have reduced phagocytosis but faster intracellular growth rate in human macrophages (Torrelles et al, 2008b).…”

Avaliação da virulência micobacteriana e modulação da resposta imune durante a infecção por isolados clínicos de Mycobacterium bovis e Mycobacterium tuberculosis.

“…Quando os camundongos infectados foram tratados com anti-IFN, a resposta imune do tipo Th1 foi restaurada e, consequentemente, observado o aumento da sobrevivência dos animais (Manca et al, 2001;Manca et al, 2005). Reed et al (2004) mostraram que a falha da resposta imune durante a infecção pelo isolado HN878 era devida à expressão de PGL. Neste isolado, a ausência da expressão de PGL pela micobactéria levou à perda da hipervirulência, correlacionando com o aumento da ativação dos macrófagos.…”

“…Ordway et al (2007) mostraram que o isolado clínico de genótipo Beijing HN878 foi capaz de induzir ativação exacerbada da resposta imune do tipo Th1, seguida de regulação negativa desta resposta em camundongos C57BL/6. A mortalidade nestes animais foi semelhante à observada por Manca et al (2001Manca et al ( , 2005 e Reed et al (2004). Foi confirmado, por Ordway et al (2007), que na ausência de IFN tipo 1 há o aumento da sobrevivência dos animais devido à ativação da resposta imune do tipo Th1 e baixa contagem bacilar no pulmão.…”