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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)
 
Gene Review

prfA  -  listeriolysin regulatory protein

Listeria monocytogenes serotype 4b str. F2365

 
 
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Disease relevance of prfA

  • A prfA transposon mutant of Listeria monocytogenes F2365, a serotype 4b strain, is able to survive in the gastrointestinal tract but does not cause systemic infection of the spleens and livers of intragastrically inoculated mice [1].
  • We demonstrate here that a hly-lacZ fusion introduced into Bacillus subtilis is strongly activated when the prfA gene product is supplied in trans under the control of an isopropyl-beta-D-thiogalactopyranoside-inducible promoter, Pspac [2].
 

High impact information on prfA

  • Here, we show that the untranslated mRNA (UTR) preceding prfA, forms a secondary structure, which masks the ribosome binding region [3].
  • New Listeria monocytogenes prfA* mutants, transcriptional properties of PrfA* proteins and structure-function of the virulence regulator PrfA [4].
  • Analyses using an L. monocytogenes strain in which the prfA gene is expressed constitutively at 37 degrees C from a plasmid indicate that the autoregulatory substance represses PrfA-dependent expression by inhibiting PrfA activity [5].
  • To gain a deeper understanding of the PrfA regulon, we constructed a whole-genome array based on the complete genome sequence of Listeria monocytogenes strain EGDe and evaluated the expression profiles of the wild-type EGDe and a prfA-deleted mutant (EGDe Delta prfA) [6].
  • The activation of HUVEC required viable bacteria and was abolished in prfA-deficient mutants of L. monocytogenes, suggesting that virulence genes are associated with endothelial cell activation [7].
 

Biological context of prfA

  • prfA is a member of the Crp/Fnr family of global regulatory genes in Listeria monocytogenes that has been shown previously to regulate several key virulence determinants both in vitro and in parenterally inoculated laboratory rodents [1].
  • In summary (i) sigmaB is primarily activated during environmental stress and does not contribute to PrfA activation in intracellular L. monocytogenes and (ii) the partially sigmaB-dependent P2prfA promoter region contributes the majority of prfA transcripts in both intra- and extracellular bacteria [8].
  • These results demonstrate that virulence gene activation does not depend only on prfA transcript accumulation [9].
  • The ability to induce cellular apoptosis was retained by all mutants tested, except the prfA and delta hly mutants, both of which are unable to produce listeriolysin [10].
  • Detection of a prfA-independent promoter responsible for listeriolysin gene expression in mutant Listeria monocytogenes strains lacking the PrfA regulator [11].
 

Anatomical context of prfA

  • These findings indicate that the global regulatory gene prfA is dispensable for colonization of the GI tract in mice but not for systemic infection [1].
  • Survival of the prfA mutant in synthetic gastric fluid at pH 2.5 or 5 was somewhat reduced compared to that of the wild-type strain, as was its ability to invade and multiply within differentiated human intestinal epithelial cells (Caco-2 cells) [1].
  • We found that the prfA mutant was able to survive in the GI tract (i.e., cecum) of mice, albeit in numbers somewhat less than those of the wild-type parent strain of L. monocytogenes [1].
  • Increased plcA transcript levels, which were similar in both host cell vacuole and cytosol, were associated with increases in both prfA expression and PrfA activity. qRT-PCR assays were designed to measure expression of prfA from each of its three promoter regions [8].
  • Internalin-mediated invasion of epithelial cells by Listeria monocytogenes is regulated by the bacterial growth state, temperature and the pleiotropic activator prfA [12].
 

Associations of prfA with chemical compounds

  • This substitution inactivated PrfA, since expression of the PrfAK220T mutant gene in an EGDDeltaprfA strain did not restore the haemolytic and phosphatidylcholine phospholipase C activities, in contrast to the wild-type prfA gene [13].
 

Regulatory relationships of prfA

  • Therefore, NCTC 7973 and 10403S have genetic differences in at least two loci: one in prfA that affects carbon source regulation of virulence genes and another in an unidentified gene(s) that up-regulates alpha-glucosidase activity [14].
  • This strain was rapidly killed when expression of iap was induced by introduction of a second plasmid carrying prfA [15].
  • In order to test whether the catabolite co-repressor P-Ser-HPr might be involved in PrfA regulation, we used a Bacillus subtilis strain (BUG1199) containing L. monocytogenes prfA under control of pspac and the lacZ reporter gene fused to the PrfA-activated hly promoter [16].
 

Other interactions of prfA

  • Microvilli played an active role in the phagocytosis of the prfA* strain, and actA was required for their remodelling into pseudopods mediating bacterial uptake [17].
  • In order to avoid a possible failure in the detection of virulent L. monocytogenes, a one-step procedure which enabled demonstration of three virulence-associated genes, prfA, hlyA, and plcB, simultaneously in a single PCR mixture was developed [18].
  • The life-time of the prfA, plcA, and mpl transcripts is short [19].
  • However, the prfA genotype does not affect the regulation of alpha-glucosidase activity by repressing sugars [14].
  • Two classes of B. subtilis survivor mutants were identified: one carried mutations in iap, and the second carried mutations in prfA [15].
 

Analytical, diagnostic and therapeutic context of prfA

  • However, these mutants were fully virulent both in an animal model and in tissue culture models of infection, suggesting that the two prfA promoters are functionally redundant in vivo [20].
  • Scanning electron microscopy of infected Caco-2 human enterocytes suggested that this pathway involves microvilli. prfA* bacteria, but not wild-type bacteria (which express PrfA-dependent genes very weakly in vitro) or prfA* DeltaactA bacteria, efficiently invaded differentiated Caco-2 cells via their apical surface [17].
  • The expression of three L. monocytogenes genes, iap, hly, and prfA, was examined to determine a suitable target for amplification of RT-PCR [21].

References

  1. A prfA transposon mutant of Listeria monocytogenes F2365, a serotype 4b strain, is able to survive in the gastrointestinal tract but does not cause systemic infection of the spleens and livers of intragastrically inoculated mice. Faith, N., Uhlich, G., Luchansky, J.B., Neudeck, B., Czuprynski, C. Infect. Immun. (2005) [Pubmed]
  2. Transcriptional activation of the Listeria monocytogenes hemolysin gene in Bacillus subtilis. Freitag, N.E., Youngman, P., Portnoy, D.A. J. Bacteriol. (1992) [Pubmed]
  3. An RNA thermosensor controls expression of virulence genes in Listeria monocytogenes. Johansson, J., Mandin, P., Renzoni, A., Chiaruttini, C., Springer, M., Cossart, P. Cell (2002) [Pubmed]
  4. New Listeria monocytogenes prfA* mutants, transcriptional properties of PrfA* proteins and structure-function of the virulence regulator PrfA. Vega, Y., Rauch, M., Banfield, M.J., Ermolaeva, S., Scortti, M., Goebel, W., Vázquez-Boland, J.A. Mol. Microbiol. (2004) [Pubmed]
  5. Negative control of Listeria monocytogenes virulence genes by a diffusible autorepressor. Ermolaeva, S., Novella, S., Vega, Y., Ripio, M.T., Scortti, M., Vázquez-Boland, J.A. Mol. Microbiol. (2004) [Pubmed]
  6. Transcriptome analysis of Listeria monocytogenes identifies three groups of genes differently regulated by PrfA. Milohanic, E., Glaser, P., Coppée, J.Y., Frangeul, L., Vega, Y., Vázquez-Boland, J.A., Kunst, F., Cossart, P., Buchrieser, C. Mol. Microbiol. (2003) [Pubmed]
  7. Listeriolysin O-dependent activation of endothelial cells during infection with Listeria monocytogenes: activation of NF-kappa B and upregulation of adhesion molecules and chemokines. Kayal, S., Lilienbaum, A., Poyart, C., Memet, S., Israel, A., Berche, P. Mol. Microbiol. (1999) [Pubmed]
  8. Contributions of Listeria monocytogenes sigmaB and PrfA to expression of virulence and stress response genes during extra- and intracellular growth. Kazmierczak, M.J., Wiedmann, M., Boor, K.J. Microbiology (Reading, Engl.) (2006) [Pubmed]
  9. Five Listeria monocytogenes genes preferentially expressed in infected mammalian cells: plcA, purH, purD, pyrE and an arginine ABC transporter gene, arpJ. Klarsfeld, A.D., Goossens, P.L., Cossart, P. Mol. Microbiol. (1994) [Pubmed]
  10. Apoptosis of mouse dendritic cells is triggered by listeriolysin, the major virulence determinant of Listeria monocytogenes. Guzmán, C.A., Domann, E., Rohde, M., Bruder, D., Darji, A., Weiss, S., Wehland, J., Chakraborty, T., Timmis, K.N. Mol. Microbiol. (1996) [Pubmed]
  11. Detection of a prfA-independent promoter responsible for listeriolysin gene expression in mutant Listeria monocytogenes strains lacking the PrfA regulator. Domann, E., Wehland, J., Niebuhr, K., Haffner, C., Leimeister-Wächter, M., Chakraborty, T. Infect. Immun. (1993) [Pubmed]
  12. Internalin-mediated invasion of epithelial cells by Listeria monocytogenes is regulated by the bacterial growth state, temperature and the pleiotropic activator prfA. Dramsi, S., Kocks, C., Forestier, C., Cossart, P. Mol. Microbiol. (1993) [Pubmed]
  13. A naturally occurring mutation K220T in the pleiotropic activator PrfA of Listeria monocytogenes results in a loss of virulence due to decreasing DNA-binding affinity. Velge, P., Herler, M., Johansson, J., Roche, S.M., Témoin, S., Fedorov, A.A., Gracieux, P., Almo, S.C., Goebel, W., Cossart, P. Microbiology (Reading, Engl.) (2007) [Pubmed]
  14. Regulation of hly expression in Listeria monocytogenes by carbon sources and pH occurs through separate mechanisms mediated by PrfA. Behari, J., Youngman, P. Infect. Immun. (1998) [Pubmed]
  15. Positive selection of mutations leading to loss or reduction of transcriptional activity of PrfA, the central regulator of Listeria monocytogenes virulence. Herler, M., Bubert, A., Goetz, M., Vega, Y., Vazquez-Boland, J.A., Goebel, W. J. Bacteriol. (2001) [Pubmed]
  16. How seryl-phosphorylated HPr inhibits PrfA, a transcription activator of Listeria monocytogenes virulence genes. Herro, R., Poncet, S., Cossart, P., Buchrieser, C., Gouin, E., Glaser, P., Deutscher, J. J. Mol. Microbiol. Biotechnol. (2005) [Pubmed]
  17. A role for ActA in epithelial cell invasion by Listeria monocytogenes. Suárez, M., González-Zorn, B., Vega, Y., Chico-Calero, I., Vázquez-Boland, J.A. Cell. Microbiol. (2001) [Pubmed]
  18. Detection of multiple virulence-associated genes of Listeria monocytogenes by PCR in artificially contaminated milk samples. Cooray, K.J., Nishibori, T., Xiong, H., Matsuyama, T., Fujita, M., Mitsuyama, M. Appl. Environ. Microbiol. (1994) [Pubmed]
  19. Transcriptional regulation of prfA and PrfA-regulated virulence genes in Listeria monocytogenes. Bohne, J., Sokolovic, Z., Goebel, W. Mol. Microbiol. (1994) [Pubmed]
  20. Dual promoters of the Listeria monocytogenes prfA transcriptional activator appear essential in vitro but are redundant in vivo. Freitag, N.E., Portnoy, D.A. Mol. Microbiol. (1994) [Pubmed]
  21. Sensitive detection of viable Listeria monocytogenes by reverse transcription-PCR. Klein, P.G., Juneja, V.K. Appl. Environ. Microbiol. (1997) [Pubmed]
 
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