Listeriolysin O
Encyclopedia
Listeriolysin O 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.
-activated, cholesterol
-dependent, pore-forming toxin protein
; hence, it is activated by reducing agent
s and inhibited by oxidizing agent
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
s (average pH ~ 5.9) of cells that have phagocytosed 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 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. 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.
called LIPI-1. 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.
Hemolysin
Hemolysins are exotoxins produced by bacteria that cause lysis of red blood cells in vitro. Visualization of hemolysis of red blood cells in agar plates facilitates the categorization of some pathogenic bacteria such as Streptococcus and Staphylococcus...
produced by the bacterium Listeria monocytogenes, the pathogen responsible for causing listeriosis. The toxin
Exotoxin
An exotoxin is a toxin excreted by a microorganism, like bacteria, fungi, algae, and protozoa. An exotoxin can cause damage to the host by destroying cells or disrupting normal cellular metabolism. They are highly potent and can cause major damage to the host...
may be considered a virulence factor
Virulence factor
Virulence factors are molecules expressed and secreted by pathogens that enable them to achieve the following:* colonization of a niche in the host...
, since it is crucial for the virulence
Virulence
Virulence is by MeSH definition the degree of pathogenicity within a group or species of parasites as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host. The pathogenicity of an organism - its ability to cause disease - is determined by its...
of L. monocytogenes.
Biochemistry
Listeriolysin O is a non-enzymatic, cytolytic, thiolThiol
In organic chemistry, a thiol is an organosulfur compound that contains a carbon-bonded sulfhydryl group...
-activated, cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
-dependent, pore-forming toxin protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
; hence, it is activated by reducing agent
Reducing agent
A reducing agent is the element or compound in a reduction-oxidation reaction that donates an electron to another species; however, since the reducer loses an electron we say it is "oxidized"...
s and inhibited by oxidizing agent
Oxidizing agent
An oxidizing agent can be defined as a substance that removes electrons from another reactant in a redox chemical reaction...
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
Phagosome
In cell biology, a phagosome is a vacuole formed around a particle absorbed by phagocytosis. The vacuole is formed by the fusion of the cell membrane around the particle. A phagosome is a cellular compartment in which pathogenic microorganisms can be killed and digested...
s (average pH ~ 5.9) of cells that have phagocytosed 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 reduced activity in the more basic cytosol
Cytosol
The cytosol or intracellular fluid is the liquid found inside cells, that is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrion into compartments....
.
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
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
factors such as the complement system
Complement system
The complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the immune system called the innate immune system that is not adaptable and does not change over the course of an individual's lifetime...
and antibodies
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
.
LLO also causes dephosphorylation of histone
Histone
In biology, histones are highly alkaline proteins found in eukaryotic cell nuclei that package and order the DNA into structural units called nucleosomes. They are the chief protein components of chromatin, acting as spools around which DNA winds, and play a role in gene regulation...
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
PEST sequence
A PEST sequence is a peptide sequence which is rich in proline , glutamic acid , serine , and threonine . This sequence is associated with proteins that have a short intracellular half-life; hence, it is hypothesized that the PEST sequence acts as a signal peptide for protein degradation.The...
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 islandPathogenicity island
Pathogenicity islands are a distinct class of genomic islands acquired by microorganisms through horizontal gene transfer. They are incorporated in the genome of pathogenic organisms but are usually absent from those non-pathogenic organisms of the same or closely related species...
called LIPI-1. Transcription
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
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
PrfA thermoregulator UTR
The PrfA thermoregulator UTR is an RNA thermometer found in the 5' UTR of the prfA gene. In Listeria monocytogenes, virulence genes are maximally expressed at 37°C but are almost silent at 30°C. The genes are controlled by PrfA, a transcriptional activator whose expression is thermoregulated...
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.
External links
- Todar's Online Textbook of Bacteriology - "Listeria monocytogenes and Listeriosis"