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Gene Review

hly  -  listeriolysin O

Listeria monocytogenes serotype 4b str. F2365

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Disease relevance of hly

  • We found that the placenta was highly susceptible to bacteria, including avirulent bacteria, such as an L. monocytogenes mutant with an hly deletion (DeltaLLO) and a nonpathogenic species, Listeria innocua, suggesting that permissive trophoblastic cells, trapping bacteria, provide a protective niche for bacterial survival [1].
  • A unique nonsynonymous mutation was found in the hly gene of L. monocytogenes isolates that were associated with the 1985 California outbreak and were the epidemic phage type [2].
  • Methods for curing endogenous prophages from the comK attachment site in 10403S-derived strains were developed. pPL1 was used to introduce the hly and actA genes at comK-attBB' in deletion strains derived from 10403S and SLCC-5764 [3].
  • Bacillus subtilis strains expressing listeriolysin O (LLO) and simultaneously LLO and p60 protein were constructed [4].
  • The hly and actA genes were transcriptionally fused to Escherichia coli lacZ and Bacillus pumilus cat-86 (cat), and the fusions were integrated in single copies into the L. monocytogenes chromosome [5].

High impact information on hly


Chemical compound and disease context of hly


Biological context of hly

  • It is shown that PrfA protein is able to bind, independently of additional factors, to a 109bp DNA fragment including the entire hly promoter sequence with the anticipated PrfA binding site ('PrfA-box') [14].
  • The addition of a Paf-containing extract does not lead to significant protein binding to these two hly target sequences in the absence of PrfA but converts the complex (CIII) consisting of PrfA and the 109 bp hly DNA fragment to a slower migrating PrfA-Paf-DNA complex (CI) [14].
  • DNase I footprint experiments show that purified PrfA protects sequences of dyad symmetry previously proposed as PrfA binding sites in the hly and in the inlA promoter regions [14].
  • A total of 133 Listeria monocytogenes isolates were characterized by ribotyping and allelic analysis of the virulence genes hly, actA, and inlA to uncover linkages between independent phylogenetic and specific virulence markers [15].
  • The r-BCG strains pAT261:Hly or pMV306:Hly expressed plasmid multicopies or chromosomal single copies of the hly gene, respectively [16].

Anatomical context of hly

  • Several bacterial proteins contributing to these events have been identified, including the invasion proteins internalin A (InlA) and B (InlB), the secreted pore-forming toxin listeriolysin O (LLO) which promotes the escape from the phagocytic vacuole, and the surface protein ActA which is required for actin polymerization and bacterial movement [17].
  • The hemolytic activity of LLO in the presence of p60 protein decreased which indicates that p60 promoted adhesion and subsequent invasion of professional phagocytes [4].
  • E. coli diamenopimelate (dap) auxotroph, harboring plasmid pGB2Omegainv-hly, express the inv gene from Yersinia pseudotubercolosis that confers the ability to invade nonprofessional phagocytic cells and the hly gene from Listeria monocytogenes that allows expression of lystreriolysin O, a perforin cytolysin able to perfore phagosomal membranes [18].
  • In contrast, both fusions were active in the cytosol of J774 cells, and the activity of the actA fusion was approximately 3-fold higher than that of the hly fusion under these conditions [5].
  • When 3T6 fibroblasts were transfected with the hly gene without the 5' signal sequence, inhibition of growth, lack of cell layer confluency, and altered (spherical) cell morphology were observed [19].

Associations of hly with chemical compounds

  • Moreover, concentrations of cellobiose and other sugars required for repression of hly expression (> 1 mM) were found to significantly enhance growth of L. monocytogenes cultures, suggesting that the repression phenomenon probably results from a metabolic effect of sugar utilization rather than a signal-sensing response [20].
  • By using the hly-based system as an in vivo expression technology tool, nine in vivo-induced loci of L. monocytogenes were identified, including genes encoding (i) the previously known in vivo-inducible phosphatidylinositol phospholipase C and (ii) a putative N-acetylglucosamine epimerase, possibly involved in teichoic acid biosynthesis [21].
  • Surprisingly, hly expression was still repressed by glucose, as observed for the parental strain [22].
  • An exotoxin from a Gram-positive organism, listeriolysin-o, and the lipopolysaccharide (LPS) endotoxin from a Gram-negative organism were also effective. gamma/delta T cell responses to LPS were under lps gene control [23].
  • Here we describe the pH-dependence of vacuolar perforation by LLO, using the membrane-impermeant fluorophore 8-hydroxypyrene-1,3,6-trisulfonic acid (HPTS) to monitor the pH and integrity of vacuoles in mouse bone marrow-derived macrophages [24].

Regulatory relationships of hly

  • Finally, in comparison to induction in broth cultures, actA was highly induced (226-fold) and hly was moderately induced (20-fold) in J774 cells [5].
  • 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 [25].
  • A plasmid in which the iap gene is placed under the control of the PrfA-dependent hly promoter was constructed and introduced into B. subtilis [26].
  • IFN-beta pretreatment enhanced LLO-mediated signaling through this pathway, consistent with its ability to increase membrane damage. p38MAPK activation in response to LLO was independent of TLR4, a putative LLO receptor, and inhibition of p38MAPK neither enhanced nor prevented LLO-induced death [27].

Other interactions of hly

  • How InlA, InlB, LLO or ActA interact with the mammalian cells is beginning to be deciphered [17].
  • Specific binding of PrfA-containing extracts from strain EGD to the hly and actA promoter sequences was strongly inhibited by iron, whereas that of extracts from strain NCTC 7973 was only slightly reduced [28].
  • The most discriminatory 600-bp fragments identified in the housekeeping and stress response genes differentiated the isolates into 8 to 10 subtypes; intergenic region sequences yielded 8 and 12 allelic types based on 335- and 242-bp sequences for hly-mpl and plcA-hly, respectively [29].
  • 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 [30].
  • Genes iap, hly, plcB, InlA and InlB of L. monocytogenes 10403S had higher homology to those of strain EGD (>98%) than isolate H4 [31].

Analytical, diagnostic and therapeutic context of hly


  1. ActA is required for crossing of the fetoplacental barrier by Listeria monocytogenes. Le Monnier, A., Autret, N., Join-Lambert, O.F., Jaubert, F., Charbit, A., Berche, P., Kayal, S. Infect. Immun. (2007) [Pubmed]
  2. Identification and characterization of nucleotide sequence differences in three virulence-associated genes of listeria monocytogenes strains representing clinically important serotypes. Vines, A., Swaminathan, B. Curr. Microbiol. (1998) [Pubmed]
  3. Construction, characterization, and use of two Listeria monocytogenes site-specific phage integration vectors. Lauer, P., Chow, M.Y., Loessner, M.J., Portnoy, D.A., Calendar, R. J. Bacteriol. (2002) [Pubmed]
  4. Listeria monocytogenes protein p60 affects hemolytic activity and uptake of bacteria by macrophages. Krawczyk-Balska, A., Markiewicz, Z., Bielecki, J. Folia Microbiol. (Praha) (2005) [Pubmed]
  5. Expression of listeriolysin O and ActA by intracellular and extracellular Listeria monocytogenes. Moors, M.A., Levitt, B., Youngman, P., Portnoy, D.A. Infect. Immun. (1999) [Pubmed]
  6. A PEST-like sequence in listeriolysin O essential for Listeria monocytogenes pathogenicity. Decatur, A.L., Portnoy, D.A. Science (2000) [Pubmed]
  7. Intracellular antibody neutralizes Listeria growth. Edelson, B.T., Unanue, E.R. Immunity (2001) [Pubmed]
  8. Type I interferon sensitizes lymphocytes to apoptosis and reduces resistance to Listeria infection. Carrero, J.A., Calderon, B., Unanue, E.R. J. Exp. Med. (2004) [Pubmed]
  9. The bvr locus of Listeria monocytogenes mediates virulence gene repression by beta-glucosides. Brehm, K., Ripio, M.T., Kreft, J., Vázquez-Boland, J.A. J. Bacteriol. (1999) [Pubmed]
  10. The Listeria monocytogenes hemolysin has an acidic pH optimum to compartmentalize activity and prevent damage to infected host cells. Glomski, I.J., Gedde, M.M., Tsang, A.W., Swanson, J.A., Portnoy, D.A. J. Cell Biol. (2002) [Pubmed]
  11. Molecular basis of listeriolysin O pH dependence. Schuerch, D.W., Wilson-Kubalek, E.M., Tweten, R.K. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  12. Mechanisms of T cell epitope immunodominance analyzed in murine listeriosis. Safley, S.A., Jensen, P.E., Reay, P.A., Ziegler, H.K. J. Immunol. (1995) [Pubmed]
  13. Attenuated mutants of the intracellular bacterium Listeria monocytogenes obtained by single amino acid substitutions in listeriolysin O. Michel, E., Reich, K.A., Favier, R., Berche, P., Cossart, P. Mol. Microbiol. (1990) [Pubmed]
  14. Differential interaction of the transcription factor PrfA and the PrfA-activating factor (Paf) of Listeria monocytogenes with target sequences. Dickneite, C., Böckmann, R., Spory, A., Goebel, W., Sokolovic, Z. Mol. Microbiol. (1998) [Pubmed]
  15. Ribotypes and virulence gene polymorphisms suggest three distinct Listeria monocytogenes lineages with differences in pathogenic potential. Wiedmann, M., Bruce, J.L., Keating, C., Johnson, A.E., McDonough, P.L., Batt, C.A. Infect. Immun. (1997) [Pubmed]
  16. Mycobacterium bovis Bacille Calmette-Guérin strains secreting listeriolysin of Listeria monocytogenes. Hess, J., Miko, D., Catic, A., Lehmensiek, V., Russell, D.G., Kaufmann, S.H. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  17. Interactions of Listeria monocytogenes with mammalian cells during entry and actin-based movement: bacterial factors, cellular ligands and signaling. Cossart, P., Lecuit, M. EMBO J. (1998) [Pubmed]
  18. Engineered E. coli delivers therapeutic genes to the colonic mucosa. Castagliuolo, I., Beggiao, E., Brun, P., Barzon, L., Goussard, S., Manganelli, R., Grillot-Courvalin, C., Palù, G. Gene Ther. (2005) [Pubmed]
  19. Mammalian cells transfected with the listeriolysin gene exhibit enhanced proliferation and focus formation. Demuth, A., Chakraborty, T., Krohne, G., Goebel, W. Infect. Immun. (1994) [Pubmed]
  20. Carbon-source regulation of virulence gene expression in Listeria monocytogenes. Milenbachs, A.A., Brown, D.P., Moors, M., Youngman, P. Mol. Microbiol. (1997) [Pubmed]
  21. Listeriolysin O as a reporter to identify constitutive and in vivo-inducible promoters in the pathogen Listeria monocytogenes. Dubail, I., Berche, P., Charbit, A. Infect. Immun. (2000) [Pubmed]
  22. Identification of a new locus in Listeria monocytogenes involved in cellobiose-dependent repression of hly expression. Huillet, E., Larpin, S., Pardon, P., Berche, P. FEMS Microbiol. Lett. (1999) [Pubmed]
  23. Induction of murine peritoneal gamma/delta T cells and their role in resistance to bacterial infection. Skeen, M.J., Ziegler, H.K. J. Exp. Med. (1993) [Pubmed]
  24. pH-dependent perforation of macrophage phagosomes by listeriolysin O from Listeria monocytogenes. Beauregard, K.E., Lee, K.D., Collier, R.J., Swanson, J.A. J. Exp. Med. (1997) [Pubmed]
  25. 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]
  26. 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]
  27. IFN-beta increases listeriolysin O-induced membrane permeabilization and death of macrophages. Zwaferink, H., Stockinger, S., Hazemi, P., Lemmens-Gruber, R., Decker, T. J. Immunol. (2008) [Pubmed]
  28. Specific binding of the Listeria monocytogenes transcriptional regulator PrfA to target sequences requires additional factor(s) and is influenced by iron. Böckmann, R., Dickneite, C., Middendorf, B., Goebel, W., Sokolovic, Z. Mol. Microbiol. (1996) [Pubmed]
  29. Rational design of DNA sequence-based strategies for subtyping Listeria monocytogenes. Cai, S., Kabuki, D.Y., Kuaye, A.Y., Cargioli, T.G., Chung, M.S., Nielsen, R., Wiedmann, M. J. Clin. Microbiol. (2002) [Pubmed]
  30. 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]
  31. Virulence phenotyping and molecular characterization of a low-pathogenicity isolate of Listeria monocytogenes from cow's milk. Jiang, L.L., Xu, J.J., Chen, N., Shuai, J.B., Fang, W.H. Acta Biochim. Biophys. Sin. (Shanghai) (2006) [Pubmed]
  32. Use of listeriolysin O and internalin A in a seroepidemiological study of listeriosis in Swiss dairy cows. Boerlin, P., Boerlin-Petzold, F., Jemmi, T. J. Clin. Microbiol. (2003) [Pubmed]
  33. PrfA mediates specific binding of RNA polymerase of Listeria monocytogenes to PrfA-dependent virulence gene promoters resulting in a transcriptionally active complex. Böckmann, R., Dickneite, C., Goebel, W., Bohne, J. Mol. Microbiol. (2000) [Pubmed]
  34. Presentation of Listeria monocytogenes antigens by major histocompatibility complex class I molecules to CD8 cytotoxic T lymphocytes independent of listeriolysin secretion and virulence. Szalay, G., Hess, J., Kaufmann, S.H. Eur. J. Immunol. (1994) [Pubmed]
  35. Detection of Listeria monocytogenes from a model food by fluorescence resonance energy transfer-based PCR with an asymmetric fluorogenic probe set. Koo, K., Jaykus, L.A. Appl. Environ. Microbiol. (2003) [Pubmed]
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