Listeriolysin O

Listeriolysin O (LLO) is a hemolysin produced by the bacterium Listeria monocytogenes, the pathogen responsible for causing listeriosis. The toxin may be considered a virulence factor, since it is crucial for the virulence of L. monocytogenes.^[1]

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Biochemistry

Listeriolysin O is a thiol-activated cholesterol-dependent pore forming toxin protein; hence, it is activated by reducing agents and inhibited by oxidizing agents.^[2] However, LLO differs from other thiol-activated toxins, since its cytolytic activity is maximized at a pH of 5.5.^[2].

By maximizing activity at a pH of 5.5, LLO is selectively activated within the acidic phagosomes (average pH ~ 5.9) of cells that have phagocytosed L. monocytogenes.^[3] After LLO lyses the phagosome, the bacterium escapes into the cytosol, where it can grow intracellularly. Upon release from the phagosome, the toxin has reduced activity in the more basic cytosol.

Hence, LLO permits L. monocytogenes to escape from phagosomes into the cytosol without damaging the plasma membrane of the infected cell. This allows the bacteria to live intracellularly, where they are protected from extracellular immune system factors such as the complement system and antibodies.

LLO also causes dephosphorylation of histone H3 and deacetylation of histone H4 during the early phases of infection, prior to entry of L. monocytogenes into the host cell.^[4] The pore-forming activity is not involved in causing the histone modifications. The alterations of the histones cause the down regulation of genes encoding proteins involved in the inflammatory response. Thus, LLO may be important in subverting the host immune response to L. monocytogenes.^[4]

A PEST-like sequence is present in LLO and is considered essential for virulence, since mutants lacking the sequence lysed the host cell.^[5] However, contrary to PEST's supposed role in protein degradation, evidence suggests that the PEST-like sequence may regulate LLO production in the cytosol rather than increase degradation of LLO.^[6]

Regulation of expression

Listeriolysin O is encoded by the gene hly, which is part of a pathogenicity island called LIPI-1.^[7] Transcription of hly, as well as other virulence factors of L. monocytogenes within LIPI-1, is activated by the protein encoded by prfA gene. prfA is thermoregulated, such that translation of prfA maximally occurs at 37°C and is nearly silent at 30°C.^[8] Since 37°C is within the range of normal body temperature, PrfA protein, as well as listeriolysin O and other virulence factors regulated by PrfA, is only produced when L. monocytogenes is in a host.

References

1. ^ Cossart P (1988). "The listeriolysin O gene: a chromosomal locus crucial for the virulence of Listeria monocytogenes". Infection 16 Suppl 2: S157-9. PMID 2843472.
2. ^ ^{a b} Geoffroy C, Gaillard JL, Alouf JE, Berche P (1987). "Purification, characterization, and toxicity of the sulfhydryl-activated hemolysin listeriolysin O from Listeria monocytogenes". Infect. Immun. 55 (7): 1641-6. PMID 3110067.
3. ^ Dramsi S, Cossart P (2002). "Listeriolysin O: a genuine cytolysin optimized for an intracellular parasite". J. Cell Biol. 156 (6): 943-6. doi:10.1083/jcb.200202121. PMID 11901162.
4. ^ ^{a b} Hamon MA, Batsché E, Régnault B, Tham TN, Seveau S, Muchardt C, Cossart P (2007). "Histone modifications induced by a family of bacterial toxins". Proc. Natl. Acad. Sci. U.S.A. 104 (33): 13467-72. doi:10.1073/pnas.0702729104. PMID 17675409.
5. ^ Decatur AL, Portnoy DA (2000). "A PEST-like sequence in listeriolysin O essential for Listeria monocytogenes pathogenicity". Science 290 (5493): 992-5. PMID 11062133.
6. ^ Schnupf P, Portnoy DA, Decatur AL (2006). "Phosphorylation, ubiquitination and degradation of listeriolysin O in mammalian cells: role of the PEST-like sequence". Cell. Microbiol. 8 (2): 353-64. doi:10.1111/j.1462-5822.2005.00631.x. PMID 16441444.
7. ^ Virulence Factors of Pathogenic Bacteria. "Pathogenicity islands in Listeria: LIPI-1." State Key Laboratory for Molecular Virology and Genetic Engineering, Bejing, China. Last accessed June 18, 2007.
8. ^ Johansson J, Mandin P, Renzoni A, Chiaruttini C, Springer M, Cossart P (2002). "An RNA thermosensor controls expression of virulence genes in Listeria monocytogenes". Cell 110 (5): 551-61. PMID 12230973.