Listeriolysin O (LLO) is a hemolysin produced by the bacterium Listeria monocytogenes, the pathogen responsible for causing listeriosis. The Exotoxin may be considered a virulence factor, since it is crucial for the virulence of L. monocytogenes.
Biochemistry
Listeriolysin O is a non-enzymatic, cytolytic,
thiol-activated, cholesterol-dependent cytolysin; hence, it is activated by
and inhibited by
.
However, LLO differs from other thiol-activated toxins, since its cytolytic activity is maximized at a pH of 5.5.
By maximizing activity at a pH of 5.5, LLO is selectively activated within the acidic (average pH ~ 5.9) of cells that have phagocytosis L. monocytogenes.
Furthermore, 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 antibody.
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.
A PEST sequence is present in LLO and is considered essential for virulence, since mutants lacking the sequence lysed the host cell.
Regulation of expression
Listeriolysin O is encoded by the gene
hly, which is part of a pathogenicity island called LIPI-1.
[Virulence Factors of Pathogenic Bacteria. "Pathogenicity islands in Listeria: LIPI-1." State Key Laboratory for Molecular Virology and Genetic Engineering, Beijing, China. Last accessed June 18, 2007.] 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 by the PrfA thermoregulator UTR element, such that translation of
prfA maximally occurs at 37 °C and is nearly silent at 30 °C.
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.
Medical application
A recombinant
BCG vaccine against
Mycobacterium tuberculosis is being developed that expresses Listeriolysin O and lacks
Urease C. The ΔureC hly+ rBCG vaccine has significantly higher protection than the original BCG strain due to improved antigen presentation. Listeriolysin creates pores in the
phagosome and allows the bacteria to escape into the cytosol, so antigens can be presented on both Class I and Class II Major Histocompatibility Complex and activate CD8 and CD4
T-cells respectively. Urease produces
ammonia and creates a basic environment which inhibits listeriolysin activity, so it is knocked out to provide the optimal pH.
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