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Mycobacterium tuberculosis Chaperonin 60.1 has Bipolar Effects on Human peripheral blood-derived Monocytes

ABSTRACT: Chaperonin 60 (Cpn60) is a prototypic molecular chaperone essential for cellular function due to its protein folding actions. However, over the past decade it has been established that Cpn60 can be released by human cells and by certain bacteria to act as an extracellular signalling protein. Mycobacterium tuberculosis produces two Cpn60 proteins: Cpn60.1 and Cpn60.2. We recently generated a M. tuberculosis mutant with an inactivated cpn60.1 gene and demonstrated that granuloma formation was impaired after murine/guinea pig infection. This finding suggested that Cpn60.1 may interact with the cellular organisation of the host response to M. tuberculosis bacilli. In this study, we report that recombinant M. tuberculosis Cpn60.1 has both pro- and anti-inflammatory effects on human circulating monocytes. At high concentrations, recombinant Cpn60.1 induces the synthesis of TNF-α, IL6, and IL8, and promotes the phosphorylation of NF-κBp65, p44/42MAPK and p38 MAPK. At lower concentrations M. tuberculosis Cpn60.1 inhibits lipopolysaccharide-induced release of TNF-α, and monocyte transcriptional activation program. Both effects are abrogated by proteolysis of Cpn60.1 and therefore cannot be attributed to contamination with lipopolysaccharide. Competition with LPS for binding to a common receptor, the release of IL-10 or down-regulation of TLR4 on the cell surface were excluded as explanations for the inhibitory activity of Cpn60.1. We therefore conclude that M. tuberculosis Cpn60.1 is an unusual protein with the ability to induce bipolar effects on human monocytes, which may help explain the pathology of granuloma formation in tuberculosis. We used microarrays to analyse the bipolar effectsof Cpn60.1 on human monocytes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE18794 | GEO | 2015/02/17

SECONDARY ACCESSION(S): PRJNA121199

REPOSITORIES: GEO

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Project description:Myeloid dendritic cells (DC) and macrophages play an important role in pathogen sensing and antimicrobial defense. Recently we demonstrated that infection of human DC with intracellular bacterium Listeria monocytogenes (L.monocytogenes) leads to the induction of the immunoinhibitory enzyme indoleamine 2,3-dioxygenase (Popov et al., J Clin Invest, 2006), while in the previous studies L.monocytogenes infection was associated with a rather stimulatory DC phenotype. To clarify this discrepancy we performed comparative microarray analysis of immature mo-DC (immDC), mature stimulatory mo-DC (matDC) and mature inhibitory DC either stimulated with prostaglandin E2 (PGE2-DC) or infected with L.monocytogenes (infDC). Studying infection of human myeloid DC with Listeria monocytogenes, we found out, that infected DC are modified by the pathogen to express multiple inhibitory molecules, including indoleamine 2,3-dioxygenase (IDO), cyclooxygenase-2, interleukin 10 and CD25, which acts on DC as IL-2 scavenger. All these inhibitory molecules, expressed on regulatory DC (DCreg), are strictly TNF-dependent and are in concert suppressing T-cell responses. Moreover, only DCreg can efficiently control the number of intracellular listeria, mostly by IDO-mediated mechanisms and by other factors, remaining to be identified. Analyzing publicly acessible data of transcriptional changes in DC and macrophages, infected by various pathogens and parasites (GEO, GSE360), we noticed that infection of these cells with Mycobacterium tuberculosis causes transcriptional response, comparable with the one caused by listeria in human DC. In fact, granuloma in tuberculosis and listeriosis in vivo are enriched for myeloid DC and macrophages characterized by regulatory phenotype. In summary, regulatory myeloid DC and macrophages may play a dual role during life-threatening granulomatous infections, such as tuberculosis: on one hand, regulatory myeloid cells promote pathogen containment by efficiently killing intracellular bacteria, on the other hand these cells inhibit granuloma-associated T cells and thereby might be involved in the retention of TNF-controlled granuloma integrity protecting the host from granuloma break-down and pathogen dissemination. Experiment Overall Design: Transcriptional profiles of immature mo-DC (immDC, n=3), mature stimulatory mo-DC (matDC, n=3) and mature inhibitory mo-DC either stimulated with prostaglandin E2 (PGE2-DC, n=3) or infected with L.monocytogenes (infDC, n=3) were compared on Affymetrix HG-U133A platform. All samples represent biological replicates and were processed separately throughout the experiment.

Project description:Myeloid dendritic cells (DC) and macrophages play an important role in pathogen sensing and antimicrobial defense. Recently we demonstrated that infection of human DC with intracellular bacterium Listeria monocytogenes (L.monocytogenes) leads to the induction of the immunoinhibitory enzyme indoleamine 2,3-dioxygenase (Popov et al., J Clin Invest, 2006), while in the previous studies L.monocytogenes infection was associated with a rather stimulatory DC phenotype. To clarify this discrepancy we performed comparative microarray analysis of immature mo-DC (immDC), mature stimulatory mo-DC (matDC) and mature inhibitory DC either stimulated with prostaglandin E2 (PGE2-DC) or infected with L.monocytogenes (infDC). Studying infection of human myeloid DC with Listeria monocytogenes, we found out, that infected DC are modified by the pathogen to express multiple inhibitory molecules, including indoleamine 2,3-dioxygenase (IDO), cyclooxygenase-2, interleukin 10 and CD25, which acts on DC as IL-2 scavenger. All these inhibitory molecules, expressed on regulatory DC (DCreg), are strictly TNF-dependent and are in concert suppressing T-cell responses. Moreover, only DCreg can efficiently control the number of intracellular listeria, mostly by IDO-mediated mechanisms and by other factors, remaining to be identified. Analyzing publicly acessible data of transcriptional changes in DC and macrophages, infected by various pathogens and parasites (GEO, GSE360), we noticed that infection of these cells with Mycobacterium tuberculosis causes transcriptional response, comparable with the one caused by listeria in human DC. In fact, granuloma in tuberculosis and listeriosis in vivo are enriched for myeloid DC and macrophages characterized by regulatory phenotype. In summary, regulatory myeloid DC and macrophages may play a dual role during life-threatening granulomatous infections, such as tuberculosis: on one hand, regulatory myeloid cells promote pathogen containment by efficiently killing intracellular bacteria, on the other hand these cells inhibit granuloma-associated T cells and thereby might be involved in the retention of TNF-controlled granuloma integrity protecting the host from granuloma break-down and pathogen dissemination. Keywords: Cell type comparison, response to infection

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Mycobacterium tuberculosis Chaperonin 60.1 has Bipolar Effects on Human peripheral blood-derived Monocytes

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