An in vitro dual model of mycobacterial granulomas to investigate the molecular interactions between mycobacteria and human host cells

Puisségur, Marie-Pierre; Botanch, Catherine; Duteyrat, Jean-Luc; Delsol, Georges; Caratero, C; Altare, Frédéric

doi:10.1111/j.1462-5822.2004.00371.x

Cited by 151 publications

(152 citation statements)

References 17 publications

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“…Although oxygenated MA from M. tuberculosis H37Rv has been shown to modulate granuloma formation, the interacting partners from the host were unknown. Experiments in the current study involving an in vitro model of granuloma formation (16,41,47) validate the presence of the keto-MA-TR4 axis in the granuloma, as seen from the increased number of cells bound to the beads coated with keto-MA, similar to the number with the positive control TDM (Fig.3A). Furthermore, it is clear that TR4 is indispensable to keto-MA-induced granuloma formation (Fig.…”

Section: Discussionsupporting

confidence: 69%

“…Our observations thus far indicate a strong role for keto-MA in FM formation via crosstalk with TR4. To further define the role of MA, and in particular keto-MA, in granuloma induction, keto-MA-coated beads and total MA-coated beads were incubated with human PBMCs, and the formation of in vitro granulomas was monitored for 8 d as described earlier (41). Uncoated beads were used as a negative control as they have earlier been shown to have minimal recruitment of the cells.…”

Section: Keto-ma Crosstalk With Tr4 Functions In M Tuberculosis Survmentioning

confidence: 99%

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Mycobacterium tuberculosisKeto-Mycolic Acid and Macrophage Nuclear Receptor TR4 Modulate Foamy Biogenesis in Granulomas: A Case of a Heterologous and Noncanonical Ligand-Receptor Pair

Dkhar

Nanduri

Mahajan

et al. 2014

The Journal of Immunology

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The cell wall of Mycobacterium tuberculosis is configured of bioactive lipid classes that are essential for virulence and potentially involved in the formation of foamy macrophages (FMs) and granulomas. Our recent work established crosstalk between M. tuberculosis cell wall lipids and the host lipid-sensing nuclear receptor TR4. In this study, we have characterized, identified, and adopted a heterologous ligand keto-mycolic acid from among M. tuberculosis lipid repertoire for the host orphan NR TR4. Crosstalk between cell wall lipids and TR4 was analyzed by transactivation and promoter reporter assays. Mycolic acid (MA) was found to transactivate TR4 significantly compared with other cell wall lipids. Among the MA, the oxygenated form, keto-MA, was responsible for transactivation, and the identity was validated by TR4 binding assays followed by TLC and nuclear magnetic resonance. Isothermal titration calorimetry revealed that keto-MA binding to TR4 is energetically favorable. This keto-MA–TR4 axis seems to be essential to this oxygenated MA induction of FMs and granuloma formation as evaluated by in vitro and in vivo model of granuloma formation. TR4 binding with keto-MA features a unique association of host nuclear receptor with a bacterial lipid and adds to the presently known ligand repertoire beyond dietary lipids. Pharmacologic modulation of this heterologous axis may hold promise as an adjunct therapy to frontline tuberculosis drugs.

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Section: Discussionsupporting

confidence: 69%

Section: Keto-ma Crosstalk With Tr4 Functions In M Tuberculosis Survmentioning

confidence: 99%

Mycobacterium tuberculosisKeto-Mycolic Acid and Macrophage Nuclear Receptor TR4 Modulate Foamy Biogenesis in Granulomas: A Case of a Heterologous and Noncanonical Ligand-Receptor Pair

Dkhar

Nanduri

Mahajan

et al. 2014

The Journal of Immunology

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“…This idea came from our findings of the effects of Hsp60.1 on osteoclast formation (reported below). To test this proposal, we have used an in vitro human blood granuloma formation assay (Puissegur et al 2004) in which we have added wild type, mutant and complemented M. tuberculosis with blood for various times and then enumerated the numbers of multinucleate giant cells. This has revealed that the isogenic mutant lacking the Hsp60.1 protein produces less than 10% of the multinucleate giant cells generated by human blood cultured with either the wild type or complemented M. tuberculosis (Henderson, Coates, Altare, unpublished data).…”

Section: Hsp60mentioning

confidence: 99%

Unfolding the relationship between secreted molecular chaperones and macrophage activation states

Henderson

2009

Cell Stress and Chaperones

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Over the last 20 years, it has emerged that many molecular chaperones and protein-folding catalysts are secreted from cells and function, somewhat in the manner of cytokines, as pleiotropic signals for a variety of cells, with much attention being focused on the macrophage. During the last decade, it has become clear that macrophages respond to bacterial, protozoal, parasitic and host signals to generate phenotypically distinct states of activation. These activation states have been termed 'classical' and 'alternative' and represent not a simple bifurcation in response to external signals but a range of cellular phenotypes. From an examination of the literature, the hypothesis is propounded that mammalian molecular chaperones are able to induce a wide variety of alternative macrophage activation states, and this may be a system for relating cellular or tissue stress to appropriate macrophage responses to restore homeostatic equilibrium.

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“…In Hjarre's disease, mucoid E. coli has been isolated from tuberculoid lesions of the cecum and liver of chickens and turkeys, while intramuscular inoculation of pure bacterial cultures or triturated diseased tissues reproduced the disease [54][55][56] . Using an in vitro model of human granuloma [57] , CD-associated AIEC LF82 were reported to induce aggregation of infected macrophages, some of which fused to form multinucleated giant cells and subsequent recruitment of lymphocytes. Analysis of the cell aggregates indicated that they are very similar to the early stages of epithelioid granulomas [58] .…”

Section: Granuloma Formationmentioning

confidence: 99%

Role of bacteria in the etiopathogenesis of inflammatory bowel disease

Barnich

Darfeuille‐Michaud²

2007

WJG

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Increased numbers of mucosa-associated Escherichia coli are observed in both of the major inflammatory bowel diseases, Crohn's disease (CD) and ulcerative colitis (UC). A potential pathophysiological link between the presence of pathogenic invasive bacteria and genetic host susceptibility of patients with ileal CD is suspected. In CD patients, with increased ileal expression of the CEACAM6 molecule acting as a receptor recognized by type 1 pilus bacterial adhesin, and with the identification of mutations in the NOD2-encoding gene, the presence of pathogenic invasive bacteria could be the link between abnormal ileal bacterial colonization and innate immune responses to invasive bacteria. In a susceptible host, the sequential etiological steps of the disease induced by adherent-invasive E. coli (AIEC) are: (1) abnormal colonization via binding to the CEACAM6 receptor, which is overexpressed in the ileal mucosa of CD patients; (2) ability to adhere to and to invade intestinal epithelial cells, which allows bacteria to cross the mucosal barrier; (3) survival and replication within infected macrophages in the lamina propria; and (4) induction of tumor necrosis factor-α secretion and granuloma formation.

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An in vitro dual model of mycobacterial granulomas to investigate the molecular interactions between mycobacteria and human host cells

Abstract: Summary In the majority of individuals infected with

Cited by 151 publications

References 17 publications

Mycobacterium tuberculosisKeto-Mycolic Acid and Macrophage Nuclear Receptor TR4 Modulate Foamy Biogenesis in Granulomas: A Case of a Heterologous and Noncanonical Ligand-Receptor Pair

Mycobacterium tuberculosisKeto-Mycolic Acid and Macrophage Nuclear Receptor TR4 Modulate Foamy Biogenesis in Granulomas: A Case of a Heterologous and Noncanonical Ligand-Receptor Pair

Unfolding the relationship between secreted molecular chaperones and macrophage activation states

Role of bacteria in the etiopathogenesis of inflammatory bowel disease

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