c-di-AMP Secreted by Intracellular
            <i>Listeria monocytogenes</i>
            Activates a Host Type I Interferon Response

Woodward, Joshua J.; Iavarone, Anthony T.; Portnoy, Daniel A.

doi:10.1126/science.1189801

Cited by 712 publications

(796 citation statements)

References 26 publications

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“…Thus, the cell envelope stress response of L. monocytogenes appears to be activated at multiple stages of the infectious process. In accordance with this, LisRK, CesRK and VirRS have been shown to contribute to pathogenesis in mice, and several of the genes shown to be highly upregulated in response to cefuroxime exposure play important roles in virulence, including dacA, lmo2714, htrA and the dlt-operon (Abachin et al, 2002;Camejo et al, 2009;Stack et al, 2005;Wilson et al, 2006;Woodward et al, 2010).…”

Section: Discussionmentioning

confidence: 89%

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Genome-wide transcriptional profiling of the cell envelope stress response and the role of LisRK and CesRK in Listeria monocytogenes

et al. 2012

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The Gram-positive bacterium Listeria monocytogenes is widely distributed in the environment and capable of causing food-borne infections in susceptible individuals. In this study, we investigated the cell envelope stress response in L. monocytogenes. Whole-genome transcriptional profiling was performed to investigate the response upon exposure to the cell wall antibiotic cefuroxime. Differential expression (at least twofold) of 558 genes was observed, corresponding to 20 % of the L. monocytogenes genome. The majority of genes that were strongly induced by cefuroxime exposure have cell-envelope-related functions, including the dlt operon and the gene encoding penicillin-binding protein PBPD2. A large overlap was observed between the cefuroxime stimulon and genes known to be induced in L. monocytogenes in blood and during intracellular infection, indicating that the cell envelope stress response is active at various stages of the infectious process. We analysed the roles of the two-component systems LisRK and CesRK in the cell envelope response, showing that activation of the most highly cefuroxime-induced genes was LisR-and CesR-dependent. In addition, multiple VirRS-and LiaSR-regulated genes were found to be induced in response to cefuroxime exposure. In total, 53 % of the genes upregulated at least fourfold by cefuroxime exposure are under positive control by one of the four two-component systems. Using genetic analyses, we showed that several genes of the cefuroxime stimulon contribute to the innate resistance of L. monocytogenes to cefuroxime and tolerance to other cellenvelope-perturbing conditions. Collectively, these findings demonstrate central roles for twocomponent systems in orchestrating the cell envelope stress response in L. monocytogenes. INTRODUCTIONListeria monocytogenes is a Gram-positive, food-borne intracellular pathogen, causing life-threatening infections in susceptible individuals (Vázquez-Boland et al., 2001). L. monocytogenes is able to survive and propagate within many different environments, including soil, food processing environments, the gastrointestinal tract and the cytosol of mammalian cells. In order to adapt and multiply within such diverse and changing surroundings, L. monocytogenes must continuously monitor and respond to environmental signals by means of complex gene regulatory networks that coordinate the expression of specific sets of genes supporting bacterial survival and growth. The genome of L. monocytogenes encodes 14 two-component signal transduction systems and a single orphan response regulator which are thought to contribute to the coordinated response to various 3Present address: Molecular Genetics Group, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Nijenborgh 7, 9747 AG Groningen, The Netherlands. The microarrays used in this study were generated and designed as described by van der Veen et al. (2010) (GEO Platform no. GPL14687) and the microarray data from this study have been deposited in the GEO database with accession...

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Section: Discussionmentioning

confidence: 89%

“…Furthermore, we noticed that the lmo2120 gene was upregulated 4.4-fold by cefuroxime exposure (Supplementary Table S2). This gene encodes the di-adenylate cyclase DacA which activates the host cytosolic surveillance pathway during infection (Woodward et al, 2010).…”

Section: Below)mentioning

confidence: 99%

Genome-wide transcriptional profiling of the cell envelope stress response and the role of LisRK and CesRK in Listeria monocytogenes

et al. 2012

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“…There is now a large body of evidence linking nucleotides such as cAMP, cGMP, and guanosine tetra-(ppGpp) and pentaphosphate (pppGpp) to the control of fundamental metabolic pathways and stress response processes in eukaryotic and prokaryotic cells (1)(2)(3). Cyclic dinucleotides in particular have recently gained increased attention with the identification of additional nucleotides such as cyclic diadenosine monophosphate (c-di-AMP) and the hybrid c-AMP-GMP molecule in bacterial cells (4)(5)(6), as well as the discovery that cyclic dinucleotides are also produced by eukaryotic cells (7)(8)(9). The dinucleotide cyclic diguanosine monophosphate (c-di-GMP) and the molecular mechanisms by which it controls cellular pathways has been well characterized, and it is now recognized as a central regulator in bacterial cells that controls the switch from free-living planktonic to a sessile biofilm-associated lifestyles.…”

mentioning

confidence: 99%

Systematic identification of conserved bacterial c-di-AMP receptor proteins

Corrigan

Campeotto

Jeganathan

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

257

401

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Nucleotide signaling molecules are important messengers in key pathways that allow cellular responses to changing environments. Canonical secondary signaling molecules act through specific receptor proteins by direct binding to alter their activity. Cyclic diadenosine monophosphate (c-di-AMP) is an essential signaling molecule in bacteria that has only recently been discovered. Here we report on the identification of four Staphylococcus aureus c-di-AMP receptor proteins that are also widely distributed among other bacteria. Using an affinity pull-down assay we identified the potassium transporter-gating component KtrA as a c-di-AMP receptor protein, and it was further shown that this protein, together with c-di-AMP, enables S. aureus to grow in low potassium conditions. We defined the c-di-AMP binding activity within KtrA to the RCK_C ( r egulator of c onductance of K + ) domain. This domain is also found in a second S. aureus protein, a predicted cation/proton antiporter, CpaA, which as we show here also directly binds c-di-AMP. Because RCK_C domains are found in proteinaceous channels, transporters, and antiporters from all kingdoms of life, these findings have broad implications for the regulation of different pathways through nucleotide-dependent signaling. Using a genome-wide nucleotide protein interaction screen we further identified the histidine kinase protein KdpD that in many bacteria is also involved in the regulation of potassium transport and a P II-like s ignal t ransduction protein, which we renamed PstA, as c-di-AMP binding proteins. With the identification of these widely distributed c-di-AMP receptor proteins we link the c-di-AMP signaling network to a central metabolic process in bacteria.

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“…Once in the cytosol, L. monocytogenes produce cyclic diadenosine monophosphate that induces type I IFN in an IRF3-dependent, MyD88-independent manner (52)(53)(54). Interestingly, a recent study demonstrated that, in human cells, Listeria-derived DNA, rather than cyclic diadenosine monophosphate, triggers IFN-b production via cytosolic DNA sensors IFI16 and cGAS (55).…”

Section: Listeriamentioning

confidence: 99%

Interfering with Immunity: Detrimental Role of Type I IFNs during Infection

Stifter¹,

Feng²

2015

The Journal of Immunology

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Type I IFNs are known to inhibit viral replication and mediate protection against viral infection. However, recent studies revealed that these cytokines play a broader and more fundamental role in host responses to infections beyond their well-established antiviral function. Type I IFN induction, often associated with microbial evasion mechanisms unique to virulent microorganisms, is now shown to increase host susceptibility to a diverse range of pathogens, including some viruses. This article presents an overview of the role of type I IFNs in infections with bacterial, fungal, parasitic, and viral pathogens and discusses the key mechanisms mediating the regulatory function of type I IFNs in pathogen clearance and tissue inflammation.

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c-di-AMP Secreted by Intracellular Listeria monocytogenes Activates a Host Type I Interferon Response

Cited by 712 publications

References 26 publications

Genome-wide transcriptional profiling of the cell envelope stress response and the role of LisRK and CesRK in Listeria monocytogenes

Genome-wide transcriptional profiling of the cell envelope stress response and the role of LisRK and CesRK in Listeria monocytogenes

Systematic identification of conserved bacterial c-di-AMP receptor proteins

Interfering with Immunity: Detrimental Role of Type I IFNs during Infection

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