<i>Mycobacterium tuberculosis</i>controls host innate immune activation through cyclopropane modification of a glycolipid effector molecule

Rao, V. Pandu Ranga; Fujiwara, Nagatoshi; Porcelli, Steven A.; Glickman, Michael S.

doi:10.1084/jem.20041668

Cited by 217 publications

(186 citation statements)

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“…However, more recent studies have revealed novel characteristics of TDM and its ability to induce hypersensitive (immunetype) granulomas which more closely represent the pathology seen during M. tuberculosis infection (Guidry et al, 2004;Hunter et al, 2006a, b;Yamagami et al, 2001). It is likely that the physical nature of TDM plays a role in this response (Rao et al, 2005(Rao et al, , 2006. The hypersensitive response to TDM is characterized by development of larger, more complex granulomas, which are often destructive in nature and include a strong lymphocytic component.…”

Section: Discussionmentioning

confidence: 99%

“…Removal of TDM from the surface of M. tuberculosis results in enhanced trafficking to acidic vesicles and decreased survival of the organism within macrophages (Indrigo et al, 2002(Indrigo et al, , 2003. Relative to surface-associated TDM, organisms genetically altered to produce less TDM, or irregular TDM, exhibit reduced growth and survival both in vivo and in vitro (Armitige et al, 2000;Copenhaver et al, 2004;Glickman et al, 2000;Rao et al, 2005). Perhaps TDM's most interesting attribute is its ability to induce cytokine and chemokine production leading to granuloma formation in the lungs of responsive mice (Behling et al, 1993;Bekierkunst, 1968;Guidry et al, 2004;Lima et al, 2001;Perez et al, 2000;Yamagami et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

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Mycobacterial glycolipid trehalose 6,6′-dimycolate-induced hypersensitive granulomas: contribution of CD4+ lymphocytes

2007

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The granulomatous response is a characteristic histological feature of Mycobacterium tuberculosis infection responsible for organism containment. The development of cell-mediated immunity is essential for protection against disease, as well as being required for maintenance of the sequestering granulomatous response. Trehalose 6,69-dimycolate (TDM; cord factor), a glycolipid associated with the cell wall of mycobacteria, is implicated as a key immunogenic component in M. tuberculosis infection. Models of TDM-induced hypersensitive granulomatous response have similar pathologies to that of active tuberculosis infection. Prior immunization (sensitization) of mice with TDM results in exacerbated histological damage, inflammation and lymphocytic infiltration upon subsequent TDM challenge. Adoptive transfer experiments were performed to ascertain the cell phenotype governing this response; CD4 + cells were identified as critical for development of related pathology. Mice receiving CD4 + cells from donor TDMimmunized mice demonstrated significantly increased production of Th1-type cytokines IFN-c and IL-12 within the lung upon subsequent TDM challenge. Control groups receiving naïve CD4 + cells, or CD8 + or CD19 + cells isolated from TDM-immunized donors, did not exhibit an exacerbated response. The identified CD4 + cells isolated from TDM-immunized mice produced significant amounts of IFN-c and IL-2 when exposed to TDM-pulsed macrophages in vitro. These experiments provide further evidence for involvement of a cell-mediated response in TDM-induced granuloma formation, which mimics pathological damage elicited during M. tuberculosis infection. INTRODUCTIONTuberculosis is not only a disease of the past; it is a disease of the future. More than 2 million people die each year from Mycobacterium tuberculosis infection, making it the most deadly of all infectious organisms. With nearly 2 billion people infected worldwide, tuberculosis remains a serious health threat (WHO, 2006), so continued research is needed to learn how this organism evades detection and destruction within the host.The cell wall of the M. tuberculosis bacilli is rich in lipids. They constitute more than 50 % of the dry weight of the organism and have been implicated as potential virulence factors (Kolattukudy et al., 1997). More than a half a century ago, Hubert Bloch identified cord factor as a 'toxic substance' that when extracted from virulent organisms caused them to lose their virulence (Bloch, 1950), and when added during infection exacerbated disease (Bloch & Noll, 1955). This substance was later identified as the mycobacterial glycolipid trehalose 6,69-dimycolate or TDM (Noll et al., 1956). TDM has been extensively studied over the years and many unique properties have been attributed to its presence. Removal of TDM from the surface of M. tuberculosis results in enhanced trafficking to acidic vesicles and decreased survival of the organism within macrophages (Indrigo et al., 2002(Indrigo et al., , 2003. Relative to surface-associated TDM, organi...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mycobacterial glycolipid trehalose 6,6′-dimycolate-induced hypersensitive granulomas: contribution of CD4+ lymphocytes

2007

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“…The biological functions of CFAs are not clear; however, they are involved in host-pathogen interactions in some bacteria such as M. tuberculosis (Glickman et al, 2000;Rao et al, 2005). In alfalfa plant nodulation assays, the cfa1 and cfa2 mutants of S. meliloti did not show impaired nodulation or nitrogen fixation (data not shown).…”

Section: Nd* Nddmentioning

confidence: 97%

“…There is some debate as to whether an increase in cyclopropane content of bacterial membranes leads to a decrease in membrane fluidity (Loffhagen et al, 2007;Munoz-Rojas et al, 2006). Furthermore, CFAs are involved in the pathogenesis of Mycobacterium tuberculosis (Glickman et al, 2000;Rao et al, 2005) and have antifungal activity in the antagonistic fluorescent pseudomonads (Ayyadurai et al, 2007), making CFAs targets for the development of new drugs for the treatment of antibiotic-resistant strains of M. tuberculosis (Bhatt et al, 2007;Guianvarc'h et al, 2006;Sekanka et al, 2007). Since CFAs are important in bacteria-host interactions for some pathogens, we have examined their possible role in S. meliloti during the alfalfa root-nodulation symbiosis.…”

Section: Introductionmentioning

confidence: 99%

Cyclopropane fatty acyl synthase in Sinorhizobium meliloti

et al. 2009

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Cyclopropane fatty acyl synthases (CFA synthases) are enzymes that catalyse the addition of a methylene group across cis double bonds of monounsaturated fatty acyl chains in lipids. We have investigated the function of two putative genes, cfa1 and cfa2, proposed to code for CFA synthases in Sinorhizobium meliloti. Total fatty acid composition and fatty acid distributions within lipid classes for wild-type and cfa1 and cfa2 mutant strains grown under P i starvation and in acidic culture conditions were obtained by GC/MS and by infusion ESI/MS/MS, respectively. For wildtype cells and the cfa1 mutant, total cyclopropane fatty acids (CFAs) increased by 10 % and 15 % under P i starvation and acidic conditions, respectively; whereas in the cfa2 mutant, CFAs were less than 0.1 % of wild-type under both growth conditions. Reporter gene fusion experiments revealed that cfa1 and cfa2 were expressed at similar levels in free-living cells. Thus under the conditions we examined, cfa2 was required for the cyclopropanation of lipids in S. meliloti whereas the role of cfa1 remains to be determined. Analysis of intact lipids revealed that cyclopropanation occurred on cis-11-octadecenoic acid located in either the sn-1 or the sn-2 position in phospholipids and that cyclopropanation in the sn-2 position occurred to a greater extent in phosphatidylcholines and sulfoquinovosyldiacylglycerols under acidic conditions than under P i starvation. The cfa2 gene was also required for cyclopropanation of non-phosphoruscontaining lipids. Principal components analysis revealed no differences in the cyclopropanation of four lipid classes. We concluded that cyclopropanation occurred independently of the polar head group. Neither cfa1 nor cfa2 was required for symbiotic nitrogen fixation.

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“…TDM isolated from a mutant deficient in the cyclopropane synthase PcaA is hypoinflammatory for macrophages and induces less severe granulatomous inflammation, showing that the fine structure of the mycolates in these lipids directly affects pathogenesis and temporal control of the host immune activation through cyclopropane modification [75].…”

Section: Does Structure Matter?mentioning

confidence: 99%

Towards understanding the functional diversity of cell wall mycolic acids of Mycobacterium tuberculosis

Verschoor

Baird

Grooten

2012

Progress in Lipid Research

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Mycolic acids constitute the waxy layer of the outer cell wall of Mycobacterium spp and a few other genera. They are diverse in structure, providing a unique chromatographic foot-print for almost each of the more than seventy Mycobacterium species. Although mainly esterified to cell wall arabinogalactan, trehalose or glucose, some free mycolic acid is secreted during in vitro growth of M. tuberculosis. In M. tuberculosis, alpha-, keto-and methoxy-mycolic acids are the main classes, each differing in their ability to attract neutrophils, induce foamy macrophages or adopt an antigenic structure for antibody recognition. Of interest is their particular relationship to cholesterol, discovered by their ability to attract cholesterol, to bind Amphotericin B or to be recognised by monoclonal antibodies that cross-react with cholesterol. The structural elements that determine this diverse functionality include the carboxylic acid in the mycolic motif, as well as the nature and stereochemistry of the two functional groups in the merochain. The functional diversity of mycolic acid classes implies that much information may be contained in the selective expression and secretion of mycolic acids to establish tuberculosis after infection of the host. Their cholesteroid nature may relate to how they utilize host cholesterol for their persistent survival.

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Mycobacterium tuberculosiscontrols host innate immune activation through cyclopropane modification of a glycolipid effector molecule

Cited by 217 publications

References 47 publications

Mycobacterial glycolipid trehalose 6,6′-dimycolate-induced hypersensitive granulomas: contribution of CD4+ lymphocytes

Mycobacterial glycolipid trehalose 6,6′-dimycolate-induced hypersensitive granulomas: contribution of CD4+ lymphocytes

Cyclopropane fatty acyl synthase in Sinorhizobium meliloti

Towards understanding the functional diversity of cell wall mycolic acids of Mycobacterium tuberculosis

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