Cyclic AMP intoxication of macrophages by a Mycobacterium tuberculosis adenylate cyclase

Agarwal, Nisheeth; Lamichhane, Gyanu; Gupta, Radhika; Nolan, Scott T.; Bishai, William R.

doi:10.1038/nature08123

Cited by 211 publications

(255 citation statements)

References 33 publications

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“…PAS inhibits Mtbdriven PGE 2 accumulation and suppresses MMP-1 secretion, suggesting that, in part, it may act as an immunomodulator to reduce tissue destruction in TB [66]. Furthermore, it has recently been demonstrated that Mtb itself produces cAMP which accesses the host cell cytoplasm to subvert the immune response [69]. One action of this pathogen-derived cAMP may be to increase MMP secretion to drive the tissue destruction that is necessary for pathogen dissemination ( fig.…”

Section: Regulation Of Mmp Expressionmentioning

confidence: 99%

Matrix metalloproteinases in tuberculosis

Elkington¹,

Ugarte-Gil²,

Friedland³

2011

European Respiratory Journal

114

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Tuberculosis (TB) remains a global health pandemic. Infection is spread by the aerosol route and Mycobacterium tuberculosis must drive lung destruction to be transmitted to new hosts. Such inflammatory tissue damage is responsible for morbidity and mortality in patients. The underlying mechanisms of matrix destruction in TB remain poorly understood but consideration of the lung extracellular matrix predicts that matrix metalloproteinases (MMPs) will play a central role, owing to their unique ability to degrade fibrillar collagens and other matrix components. Since we proposed the concept of a matrix degrading phenotype in TB a decade ago, diverse data implicating MMPs as key mediators in TB pathology have accumulated. We review the lines of investigation that have indicated a critical role for MMPs in TB pathogenesis, consider regulatory pathways driving MMPs and propose that inhibition of MMP activity is a realistic goal as adjunctive therapy to limit immunopathology in TB.

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Section: Regulation Of Mmp Expressionmentioning

confidence: 99%

Matrix metalloproteinases in tuberculosis

Elkington¹,

Ugarte-Gil²,

Friedland³

2011

European Respiratory Journal

114

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“…Consequently, intracellular cAMP concentrations in mycobacterial cells are considered to be~100-fold higher than those of other bacteria (Dass et al, 2008;Padh & Venkitasubramanian, 1976, 1980, but the significance of this is not known. Secretion of cAMP directly into host macrophages after infection has been reported and is thought to be important in tuberculosis pathogenesis (Agarwal et al, 2009;Bai et al, 2009;Lowrie et al, 1975). M. tuberculosis H37Rv contains a single CRP-FNR homologue encoded by the gene Rv3676 (Cole et al, 1998), which is 32 % identical to the E. coli CRP over 189 amino acid residues.…”

Section: Introductionmentioning

confidence: 99%

Novel regulatory roles of cAMP receptor proteins in fast-growing environmental mycobacteria

et al. 2015

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Mycobacterium smegmatis is a fast-growing, saprophytic, mycobacterial species that contains two cAMP-receptor protein (CRP) homologues designated herein as Crp1 and Crp2. Phylogenetic analysis suggests that Crp1 (Msmeg_0539) is uniquely present in fast-growing environmental mycobacteria, whereas Crp2 (Msmeg_6189) occurs in both fast-and slowgrowing species. A crp1 mutant of M. smegmatis was readily obtained, but crp2 could not be deleted, suggesting it was essential for growth. A total of 239 genes were differentially regulated in response to crp1 deletion (loss of function), including genes coding for mycobacterial energy generation, solute transport and catabolism of carbon sources. To assess the role of Crp2 in M. smegmatis, the crp2 gene was overexpressed (gain of function) and transcriptional profiling studies revealed that 58 genes were differentially regulated. Identification of the CRP promoter consensus in M. smegmatis showed that both Crp1 and Crp2 recognized the same consensus sequence (TGTGN 8 CACA). Comparison of the Crp1-and Crp2-regulated genes revealed distinct but overlapping regulons with 11 genes in common, including those of the succinate dehydrogenase operon (MSMEG_0417-0420, sdh1). Expression of the sdh1 operon was negatively regulated by Crp1 and positively regulated by Crp2. Electrophoretic mobility shift assays with purified Crp1 and Crp2 demonstrated that Crp1 binding to the sdh1 promoter was cAMP-independent whereas Crp2 binding was cAMP-dependent. These data suggest that Crp1 and Crp2 respond to distinct signalling pathways in M. smegmatis to coordinate gene expression in response to carbon and energy supply.

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“…Mycobacterium smegmatis) mycobacteria (2,3). Recent evidence has highlighted the importance of cAMP in modulating the host macrophage response to M. tuberculosis infection (4). A single adenylyl cyclase was shown to be responsible for the burst of cAMP that is seen in the macrophage following phagocytosis of M. tuberculosis, and this bacterially derived increase in cAMP was essential to attenuate the response of the macrophage to the pathogen.…”

mentioning

confidence: 99%

“…Instead, we identified a Class III phosphodiesterase, the product of the rv0805 gene (accession NP_215320), that was capable of degrading mycobacterial cAMP (6). Indeed, overexpression of Rv0805 was used to reduce intracellular levels of cAMP in M. tuberculosis to show that bacterially derived cAMP was essential to attenuate macrophage killing (4). Rv0805 is a member of the superfamily of metallophosphoesterases (MPEs) 6 that has been well characterized biochemically and structurally (7)(8)(9).…”

mentioning

confidence: 99%

A Mycobacterial Cyclic AMP Phosphodiesterase That Moonlights as a Modifier of Cell Wall Permeability

Podobnik

Tyagi

Matange

et al. 2009

Journal of Biological Chemistry

110

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Mycobacterium tuberculosis utilizes many mechanisms to establish itself within the macrophage, and bacterially derived cAMP is important in modulating the host cellular response. Although the genome of M. tuberculosis is endowed with a number of mammalian-like adenylyl cyclases, only a single cAMP phosphodiesterase has been identified that can decrease levels of cAMP produced by the bacterium. We present the crystal structure of the full-length and sole cAMP phosphodiesterase, Rv0805, found in M. tuberculosis, whose orthologs are present only in the genomes of slow growing and pathogenic mycobacteria. The dimeric core catalytic domain of Rv0805 adopts a metallophosphoesterase-fold, and the C-terminal region builds the active site and contributes to multiple substrate utilization. Localization of Rv0805 to the cell wall is dependent on its C terminus, and expression of either wild type or mutationally inactivated Rv0805 in M. smegmatis alters cell permeability to hydrophobic cytotoxic compounds. Rv0805 may therefore play a key role in the pathogenicity of mycobacteria, not only by hydrolyzing bacterial cAMP, but also by moonlighting as a protein that can alter cell wall functioning.Mycobacterium tuberculosis is probably one of the most successful human pathogens known so far, being singly responsible for the largest number of deaths worldwide due to an infectious disease. M. tuberculosis is phagocytosed by the macrophage and is able to subvert the defenses of the host by a number of mechanisms. These include the presence of a complex cell wall that prevents free passage of potentially toxic material, the ability of the bacteria to withstand the acidic environment of the phagolysosome, and to neutralize reactive oxygen and nitrogen species produced by the activated macrophage (1). An increased understanding of mechanisms utilized by this pathogen to evade the host immune system and continue to reside in the hostile environment of the macrophage, would no doubt provide avenues for the development of drugs to novel targets in the bacterium.Cross-communication between the pathogen and host could involve the utilization of signaling molecules that are conserved evolutionarily. Cyclic AMP is found in all kingdoms of life, and proteins that synthesize and degrade the cyclic nucleotide have been well characterized. The genome of M. tuberculosis H37Rv encodes 16 mammalian-like nucleotide cyclase-like genes (2), and intracellular and extracellular levels of cAMP are very high in both pathogenic and non-pathogenic (e.g. Mycobacterium smegmatis) mycobacteria (2, 3). Recent evidence has highlighted the importance of cAMP in modulating the host macrophage response to M. tuberculosis infection (4). A single adenylyl cyclase was shown to be responsible for the burst of cAMP that is seen in the macrophage following phagocytosis of M. tuberculosis, and this bacterially derived increase in cAMP was essential to attenuate the response of the macrophage to the pathogen.The regulated degradation of cAMP is as important as its synthesi...

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Cyclic AMP intoxication of macrophages by a Mycobacterium tuberculosis adenylate cyclase

Cited by 211 publications

References 33 publications

Matrix metalloproteinases in tuberculosis

Matrix metalloproteinases in tuberculosis

Novel regulatory roles of cAMP receptor proteins in fast-growing environmental mycobacteria

A Mycobacterial Cyclic AMP Phosphodiesterase That Moonlights as a Modifier of Cell Wall Permeability

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