| Listeriolysin O | |||||||
|---|---|---|---|---|---|---|---|
| Identifiers | |||||||
| Organism | Listeria monocytogenes serovar 1/2a (strain ATCC BAA-679 / EGD-e) | ||||||
| Symbol | hly | ||||||
| UniProt | P13128 | ||||||
| |||||||
Listeriolysin O (LLO) is ahemolysin produced by thebacteriumListeria monocytogenes, the pathogen responsible for causinglisteriosis. Thetoxin may be considered avirulence factor, since it is crucial for thevirulence ofL. monocytogenes.[1]
Listeriolysin O is a non-enzymatic, cytolytic,thiol-activated,cholesterol-dependent cytolysin; hence, it is activated byreducing agents and inhibited byoxidizing 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 acidicphagosomes (average pH ~ 5.9) of cells that havephagocytosedL. 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 little activity in the more basiccytosol.
Furthermore, LLO permitsL. 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 extracellularimmune system factors such as thecomplement system andantibodies.
LLO also causes dephosphorylation ofhistone H3 and deacetylation of histone H4 during the early phases of infection, prior to entry ofL. 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 toL. monocytogenes.[4]
APEST-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]
Listeriolysin O is encoded by the genehly, which is part of apathogenicity island called LIPI-1.[7]Transcription ofhly, as well as other virulence factors ofL. monocytogenes within LIPI-1, is activated by the protein encoded byprfA gene.prfA is thermoregulated by thePrfA thermoregulator UTR element, such thattranslation ofprfA maximally occurs at 37 °C and is nearly silent at 30 °C.[8] Since 37 °C is within the range ofnormal body temperature, PrfA protein, as well as listeriolysin O and other virulence factors regulated by PrfA, is only produced whenL. monocytogenes is in a host.
A recombinantBCG vaccine againstMycobacterium tuberculosis is being developed that expresses listeriolysin O and lacksurease C. The ΔureC hly+ rBCG vaccine has significantly higher protection than the original BCG strain due to improvedantigen presentation. Listeriolysin creates pores in thephagosome and allows the bacteria to escape into the cytosol, so antigens can be presented on both Class I and Class IImajor histocompatibility complex and activate CD8 and CD4T-cells respectively. Urease producesammonia and creates a basic environment which inhibits listeriolysin activity, so it is knocked out to provide the optimal pH.[9]
