Modulation of Gamma Interferon Receptor 1 by<i>Mycobacterium tuberculosis</i>: a Potential Immune Response Evasive Mechanism

Singhal, Amit; Jaiswal, Anand; Arora, Virendra K.; Prasad, H. K.

doi:10.1128/iai.01743-06

Cited by 47 publications

(60 citation statements)

References 68 publications

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“…This also results in secretion of IL-12 from infected DCs. In contrast, infection of macrophages with M. tuberculosis results in downregulation of MHC class I and II, IFN-g responsiveness, and IL-12 production (8, [41][42][43][44]. Our results also suggest that M. tuberculosis Ags expressed in infected cells at different times postinfection interact differently with DCs and macrophages, but the overall outcomes of these effects compromise the ability of the infected cell to mediate effector responses to the pathogen.…”

Section: Discussionmentioning

confidence: 47%

Suppression of TLR2-Induced IL-12, Reactive Oxygen Species, and Inducible Nitric Oxide Synthase Expression byMycobacterium tuberculosisAntigens Expressed inside Macrophages during the Course of Infection

Sharma

Singhal

et al. 2010

The Journal of Immunology

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We report the enrichment of and immune responses mediated by genes expressed by Mycobacterium tuberculosis inside macrophages as a function of time. Results indicate that M. tuberculosis expresses different genes at different times postinfection. Genes expressed early (day 1) following infection enhance M. tuberculosis-mediated activation of dendritic cells (DCs), whereas genes expressed later (day 5) in the infection prevent DC activation. However, all genes downmodulated MHC class I and II expression on infected macrophages, thus compromising their ability to interact with Ag-specific T cells. Day-1 and -5 genes downmodulated proinflammatory cytokine production from DCs, thus impairing signal 3 during DC–T cell cognate interactions. Consequently, T cells activated by Ag-experienced DCs secreted low levels of IFN-γ and IL-17 but maintained high IL-10 secretion, thus inducing suppressor responses. Further characterization revealed that day-1 and -5 genes increased TLR2-induced expression of suppressors of cytokine signaling 1 from DCs and downmodulated IL-12 expression. In addition, day-1 and -5 genes prevented the generation of reactive oxygen species in DCs. In contrast, although day-5 genes increased TLR2-mediated suppressors of cytokine signaling 1 expression in macrophages, day-1 genes downmodulated the expression of inducible NO synthase 2. Similar downregulation of immune responses was observed upon exogenous stimulation with day-1 or -5 Ags. Finally, day-1 and -5 genes promoted enhanced survival of M. tuberculosis inside DCs and macrophages. These results indicate that M. tuberculosis genes, expressed inside infected macrophages as a function of time, collectively suppress protective immune responses by using multiple and complementary mechanisms.

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Section: Discussionmentioning

confidence: 47%

Suppression of TLR2-Induced IL-12, Reactive Oxygen Species, and Inducible Nitric Oxide Synthase Expression byMycobacterium tuberculosisAntigens Expressed inside Macrophages during the Course of Infection

Sharma

Singhal

et al. 2010

The Journal of Immunology

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“…Receptors-Because the levels of cytokines and their receptors are modulated at different stages of M. tb infection (38) we next investigated the roles played by TLR2 and DC-SIGN to this end. As shown in Fig.…”

Section: Tlr2 and Dc-sign Modulate Expression Of Cytokines And Cytokinementioning

confidence: 99%

Toll-like Receptor 2 and DC-SIGNR1 Differentially Regulate Suppressors of Cytokine Signaling 1 in Dendritic Cells during Mycobacterium tuberculosis Infection

Srivastava

Manchanda

Gupta

et al. 2009

Journal of Biological Chemistry

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A major prerequisite toward development of vaccine(s) or therapeutic regimens for tuberculosis is a thorough understanding of the immune responses initiated following infection of macrophages and DCs by Mycobacterium tuberculosis (M. tb)2 (1-4). A key factor toward this is cross-regulation of cytokine secretion by different cells of the immune system (5-7). One of the molecules that regulate cytokine expression and cytokine receptor-mediated gene expression in various cells of the immune system is a family of closely related proteins called Suppressors of Cytokine Signaling (SOCS). There are currently eight members of SOCS proteins (SOCS1-7 and CIS (also called SOCS8)), with SOCS1 being the most characterized (8). All eight SOCS family members have a central Src homology 2 domain, an N-terminal domain of variable length, and a 40-amino acid motif at the C terminus known as the SOCS box. Although SOCS molecules exhibit sequence homology, particularly in the SOCS box and Src homology 2 domains, CIS and SOCS2, SOCS1 and SOCS3, SOCS4 and SOCS5, and SOCS6 and SOCS7 have marked pairwise homology across the entire protein sequence. SOCS molecules bind to the cytoplasmic tails of cytokine receptors and block their activation. This consequently leads to a block in the effects of the cytokine in question and leads to skewing of responses.Although macrophages serve as the long term hosts for mycobacteria, DCs phagocytose mycobacteria and mycobacterial antigens, and these interactions are crucial for the development of protective immunity (9 -11). As a result DC function and phenotype are modified following bacterial uptake. A number of surface receptors, e.g. Toll-like receptor (TLR) 2, mannose receptor, CD11b (Mac-1), CD11c, and DEC-205 have been implicated in mycobacterial recognition by DCs,[12][13][14].

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“…The IL-10 receptor IL10RA was downregulated in two of the pathogens, indicating a potential dampening of IL-10's antiinflammatory effects. Interestingly, all three pathogens caused the downregulation of the gamma interferon receptor IFNGR1, which Mycobacterium tuberculosis has previously been shown to downregulate as an immune evasion strategy (45).…”

Section: Vol 76 2008mentioning

confidence: 99%

The Commensal Streptococcus salivarius K12 Downregulates the Innate Immune Responses of Human Epithelial Cells and Promotes Host-Microbe Homeostasis

et al. 2008

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Modulation of Gamma Interferon Receptor 1 byMycobacterium tuberculosis: a Potential Immune Response Evasive Mechanism

Cited by 47 publications

References 68 publications

Suppression of TLR2-Induced IL-12, Reactive Oxygen Species, and Inducible Nitric Oxide Synthase Expression byMycobacterium tuberculosisAntigens Expressed inside Macrophages during the Course of Infection

Suppression of TLR2-Induced IL-12, Reactive Oxygen Species, and Inducible Nitric Oxide Synthase Expression byMycobacterium tuberculosisAntigens Expressed inside Macrophages during the Course of Infection

Toll-like Receptor 2 and DC-SIGNR1 Differentially Regulate Suppressors of Cytokine Signaling 1 in Dendritic Cells during Mycobacterium tuberculosis Infection

The Commensal Streptococcus salivarius K12 Downregulates the Innate Immune Responses of Human Epithelial Cells and Promotes Host-Microbe Homeostasis

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