Listeriolysin O (LLO) is a

hemolysin Hemolysins or haemolysins are lipids and proteins that cause lysis of red blood cells by disrupting the cell membrane. Although the lytic activity of some microbe-derived hemolysins on red blood cells may be of great importance for nutrient acqu ...

produced by the

bacterium Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were amon ...

Listeria monocytogenes ''Listeria monocytogenes'' is the species of pathogenic bacteria that causes the infection listeriosis. It is a facultative anaerobic bacterium, capable of surviving in the presence or absence of oxygen. It can grow and reproduce inside the host ...

'', the pathogen responsible for causing

listeriosis Listeriosis is a bacterial infection most commonly caused by '' Listeria monocytogenes'', although '' L. ivanovii'' and '' L. grayi'' have been reported in certain cases. Listeriosis can cause severe illness, including severe sepsis, men ...

. The

toxin A toxin is a naturally occurring organic poison produced by metabolic activities of living cells or organisms. Toxins occur especially as a protein or conjugated protein. The term toxin was first used by organic chemist Ludwig Brieger (1849 ...

may be considered a

virulence factor Virulence factors (preferably known as pathogenicity factors or effectors in plant science) are cellular structures, molecules and regulatory systems that enable microbial pathogens (bacteria, viruses, fungi, and protozoa) to achieve the following ...

, since it is crucial for the

virulence Virulence is a pathogen's or microorganism's ability to cause damage to a host. In most, especially in animal systems, virulence refers to the degree of damage caused by a microbe to its host. The pathogenicity of an organism—its ability to ...

of ''L. monocytogenes''.

Biochemistry

Listeriolysin O is a non-enzymatic, cytolytic,

thiol In organic chemistry, a thiol (; ), or thiol derivative, is any organosulfur compound of the form , where R represents an alkyl or other organic substituent. The functional group itself is referred to as either a thiol group or a sulfhydryl gro ...

-activated, cholesterol-dependent cytolysin; hence, it is activated by

reducing agent In chemistry, a reducing agent (also known as a reductant, reducer, or electron donor) is a chemical species that "donates" an electron to an (called the , , , or ). Examples of substances that are commonly reducing agents include the Earth me ...

s and inhibited by

oxidizing agent An oxidizing agent (also known as an oxidant, oxidizer, electron recipient, or electron acceptor) is a substance in a redox chemical reaction that gains or " accepts"/"receives" an electron from a (called the , , or ). In other words, an oxi ...

s. 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

phagosome In cell biology, a phagosome is a vesicle formed around a particle engulfed by a phagocyte via phagocytosis. Professional phagocytes include macrophages, neutrophils, and dendritic cells (DCs). A phagosome is formed by the fusion of the cell ...

s (average pH ~ 5.9) of cells that have

phagocytosed Phagocytosis () is the process by which a cell uses its plasma membrane to engulf a large particle (≥ 0.5 μm), giving rise to an internal compartment called the phagosome. It is one type of endocytosis. A cell that performs phagocytosis is c ...

''L. monocytogenes''. 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 basic

cytosol The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells ( intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...

. 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 The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splint ...

factors such as the complement system and antibodies. LLO also causes dephosphorylation of

histone In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn a ...

H3 and deacetylation of histone H4 during the early phases of infection, prior to entry of ''L. monocytogenes'' into the host cell. 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''. A PEST-like sequence is present in LLO and is considered essential for virulence, since mutants lacking the sequence lysed the host cell. 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.

Regulation of expression

Listeriolysin O is encoded by the gene ''hly'', which is part of a

pathogenicity island Pathogenicity islands (PAIs), as termed in 1990, are a distinct class of genomic islands acquired by microorganisms through horizontal gene transfer. Pathogenicity islands are found in both animal and plant pathogens. Additionally, PAIs are found ...

called LIPI-1.

Transcription Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including: Genetics * Transcription (biology), the copying of DNA into RNA, the fir ...

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 Translation is the communication of the meaning of a source-language text by means of an equivalent target-language text. The English language draws a terminological distinction (which does not exist in every language) between ''transla ...

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 Bacillus Calmette–Guérin (BCG) vaccine is a vaccine primarily used against tuberculosis (TB). It is named after its inventors Albert Calmette and Camille Guérin. In countries where tuberculosis or leprosy is common, one dose is recommended ...

against '' Mycobacterium tuberculosis'' is being developed that expresses Listeriolysin O and lacks

Urease Ureases (), functionally, belong to the superfamily of amidohydrolases and phosphotriesterases. Ureases are found in numerous bacteria, fungi, algae, plants, and some invertebrates, as well as in soils, as a soil enzyme. They are nickel-contai ...

C. The ΔureC hly+ rBCG vaccine has significantly higher protection than the original BCG strain due to improved

antigen presentation Antigen presentation is a vital immune process that is essential for T cell immune response triggering. Because T cells recognize only fragmented antigens displayed on cell surfaces, antigen processing must occur before the antigen fragment, n ...

. Listeriolysin creates pores in the

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 A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...

respectively. Urease produces

ammonia Ammonia is an inorganic compound of nitrogen and hydrogen with the formula . A stable binary hydride, and the simplest pnictogen hydride, ammonia is a colourless gas with a distinct pungent smell. Biologically, it is a common nitrogenous wa ...

and creates a basic environment which inhibits listeriolysin activity, so it is knocked out to provide the optimal pH.

References

External links

* Todar's Online Textbook of Bacteriology
"''Listeria monocytogenes'' and Listeriosis"
{{Toxins Bacterial toxins