Closing the loop: The PmrA/PmrB two-component system negatively controls expression of its posttranscriptional activator PmrD

Kato, Akinori; Latifi, Tammy; Groisman, Eduardo A.

doi:10.1073/pnas.0836837100

Cited by 117 publications

(123 citation statements)

References 42 publications

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“…Only when Klebsiella was grown in VMM, did the pathogen express the same lipid A pattern found in vivo as characterized by ions m/z 1,840 and m/z 1,866. Interestingly, the in vivo lipid A pattern was not observed in Klebsiella grown in a standard low magnesium medium used to study lipid A changes in other pathogens (5,6,28,29). In any case, it has been reported that Salmonella up-regulates the transcription of lpxO when growing in low magnesium medium (9).…”

Section: Discussionmentioning

confidence: 98%

Deciphering tissue-induced Klebsiella pneumoniae lipid A structure

Llobet

Martínez-Moliner

Moranta

et al. 2015

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

134

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The outcome of an infection depends on host recognition of the pathogen, hence leading to the activation of signaling pathways controlling defense responses. A long-held belief is that the modification of the lipid A moiety of the lipopolysaccharide could help Gram-negative pathogens to evade innate immunity. However, direct evidence that this happens in vivo is lacking. Here we report the lipid A expressed in the tissues of infected mice by the human pathogen Klebsiella pneumoniae. Our findings demonstrate that Klebsiella remodels its lipid A in a tissue-dependent manner. Lipid A species found in the lungs are consistent with a 2-hydroxyacyl-modified lipid A dependent on the PhoPQ-regulated oxygenase LpxO. The in vivo lipid A pattern is lost in minimally passaged bacteria isolated from the tissues. LpxO-dependent modification reduces the activation of inflammatory responses and mediates resistance to antimicrobial peptides. An lpxO mutant is attenuated in vivo thereby highlighting the importance of this lipid A modification in Klebsiella infection biology. Colistin, one of the last options to treat multidrug-resistant Klebsiella infections, triggers the in vivo lipid A pattern. Moreover, colistin-resistant isolates already express the in vivo lipid A pattern. In these isolates, LpxO-dependent lipid A modification mediates resistance to colistin. Deciphering the lipid A expressed in vivo opens the possibility of designing novel therapeutics targeting the enzymes responsible for the in vivo lipid A pattern.

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Section: Discussionmentioning

confidence: 98%

Deciphering tissue-induced Klebsiella pneumoniae lipid A structure

Llobet

Martínez-Moliner

Moranta

et al. 2015

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

134

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“…Since its first description, Edwardsiella has been characterized by a constitutive resistance to CAMPs (Muyembe et al, 1973;Reinhardt et al, 1985;Stock & Wiedemann, 2001) in contrast to the regulated resistance described in Salmonella and Yesinia (Aguirre et al, 2000;Gunn et al, 1996;Kato et al, 2003;Kox et al, 2000;Winfield et al, 2005;Wösten & Groisman, 1999). As previously mentioned, in Salmonella resistance to CAMPs is induced after exposure to sublethal concentrations of CAMPs or by inducing the activation of PhoP and RscB response regulators that upregulate the expression of the ugd gene (Gunn et al, 1996;Kox et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

“…Edwardsiella resistances to CAMPs are far higher (Table 2) compared with other resistances described in the family Enterobacteriaceae, such as Salmonella or Yersinia resistances (Aguirre et al, 2000;Gunn et al, 1996;Kato et al, 2003;Kox et al, 2000;Winfield et al, 2005;Wösten & Groisman, 1999). Since its first description, Edwardsiella has been characterized by a constitutive resistance to CAMPs (Muyembe et al, 1973;Reinhardt et al, 1985;Stock & Wiedemann, 2001) in contrast to the regulated resistance described in Salmonella and Yesinia (Aguirre et al, 2000;Gunn et al, 1996;Kato et al, 2003;Kox et al, 2000;Winfield et al, 2005;Wösten & Groisman, 1999).…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of intrinsic resistance to antimicrobial peptides of Edwardsiella ictaluri and its influence on fish gut inflammation and virulence

et al. 2013

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The genus Edwardsiella comprises a genetically distinct taxon related to other members of the family Enterobacteriaceae. It consists of bacteria differing strongly in their biochemical and physiological features, natural habitats, and pathogenic properties. Intrinsic resistance to cationic antimicrobial peptides (CAMPs) is a specific property of the genus Edwardsiella. In particular, Edwardsiella ictaluri, an important pathogen of the catfish (Ictalurus punctatus) aquaculture and the causative agent of a fatal systemic infection, is highly resistant to CAMPs. E. ictaluri mechanisms of resistance to CAMPs are unknown. We hypothesized that E. ictaluri lipopolysaccharide (LPS) plays a role in both virulence and resistance to CAMPs. The putative genes related to LPS oligo-polysaccharide (O-PS) synthesis were in-frame deleted. Individual deletions of wibT, gne and ugd eliminated synthesis of the O-PS, causing auto-agglutination, rough colonies, biofilm-like formation and motility defects. Deletion of ugd, the gene that encodes the UDP-glucose dehydrogenase enzyme responsible for synthesis of UDP-glucuronic acid, causes sensitivity to CAMPs, indicating that UDP-glucuronic acid and its derivatives are related to CAMP intrinsic resistance. E. ictaluri OP-S mutants showed different levels of attenuation, colonization of lymphoid tissues and immune protection in zebrafish (Danio rerio) and catfish. Orally inoculated catfish with O-PS mutant strains presented different degrees of gut inflammation and colonization of lymphoid tissues. Here we conclude that intrinsic resistance to CAMPs is mediated by Ugd enzyme, which has a pleiotropic effect in E. ictaluri influencing LPS synthesis, motility, agglutination, fish gut inflammation and virulence.

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“…These efforts have focused on characterizing the components and interactions for specific biological networks and their dynamical behaviors, by using standard genetic and biochemical approaches in conjunction with mathematical analysis of discovered circuits (1)(2)(3)(4)(5)(6)(7). Valuable insights into certain design features of biological networks have emerged through these efforts (8)(9)(10)(11)(12)(13) and are used to guide the design of synthetic systems (14)(15)(16). The choice of which synthetic circuits to build is often a matter of careful hand-picking guided by experimental restrictions.…”

mentioning

confidence: 99%

Highly designable phenotypes and mutational buffers emerge from a systematic mapping between network topology and dynamic output

Nochomovitz

2006

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

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Deciphering the design principles for regulatory networks is fundamental to an understanding of biological systems. We have explored the mapping from the space of network topologies to the space of dynamical phenotypes for small networks. Using exhaustive enumeration of a simple model of three-and four-node networks, we demonstrate that certain dynamical phenotypes can be generated by an atypically broad spectrum of network topologies. Such dynamical outputs are highly designable, much like certain protein structures can be designed by an unusually broad spectrum of sequences. The network topologies that encode a highly designable dynamical phenotype possess two classes of connections: a fully conserved core of dedicated connections that encodes the stable dynamical phenotype and a partially conserved set of variable connections that controls the transient dynamical flow. By comparing the topologies and dynamics of the three-and four-node network ensembles, we observe a large number of instances of the phenomenon of ''mutational buffering,'' whereby addition of a fourth node suppresses phenotypic variation amongst a set of three-node networks.designability ͉ dynamical phenotype ͉ enumeration ͉ mutational buffering ͉ regulatory network D iscerning the structure and function of cellular networks is essential to the development of a true understanding of biological systems. Experimental and theoretical studies are steadily advancing our knowledge of the wiring and input-output characteristics of a variety of natural and designed biological networks. These efforts have focused on characterizing the components and interactions for specific biological networks and their dynamical behaviors, by using standard genetic and biochemical approaches in conjunction with mathematical analysis of discovered circuits (1-7). Valuable insights into certain design features of biological networks have emerged through these efforts (8-13) and are used to guide the design of synthetic systems (14-16). The choice of which synthetic circuits to build is often a matter of careful hand-picking guided by experimental restrictions.Reverse-engineering and modeling of specific experimental systems on a case-by-case basis is necessary and meritorious. However, the space of networks and associated dynamics is potentially very large, and parallel approaches that consider broad ensembles of networks may advance our understanding of general design principles in ways that the serial strategies may have difficulty revealing. Therefore, we have chosen to explore general design principles by using a global strategy. We expect that exploration of an entire ensemble of networks and associated dynamics will reveal statistical signatures connecting network architectures to categories of dynamical phenotypes. In particular, we analyze the relationship between the space of topology and the space of dynamics by employing an analogy to the protein ''designability principle,'' which states that compact protein structures that can be encoded by a wide array of ...

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Closing the loop: The PmrA/PmrB two-component system negatively controls expression of its posttranscriptional activator PmrD

Cited by 117 publications

References 42 publications

Deciphering tissue-induced Klebsiella pneumoniae lipid A structure

Deciphering tissue-induced Klebsiella pneumoniae lipid A structure

Mechanisms of intrinsic resistance to antimicrobial peptides of Edwardsiella ictaluri and its influence on fish gut inflammation and virulence

Highly designable phenotypes and mutational buffers emerge from a systematic mapping between network topology and dynamic output

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