Listeriolysin O

Last updated
Listeriolysin O
Identifiers
Organism Listeria monocytogenes serovar 1/2a (strain ATCC BAA-679 / EGD-e)
Symbolhly
UniProt P13128

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]

Contents

Biochemistry

Listeriolysin O is a non-enzymatic, cytolytic, thiol-activated, cholesterol-dependent cytolysin; 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 little activity in the more basic cytosol.

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 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 by the PrfA thermoregulator UTR element, 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.

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. [9]

Related Research Articles

<i>Listeria monocytogenes</i> Species of pathogenic bacteria that causes the infection listeriosis

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's cells and is one of the most virulent foodborne pathogens: 20 to 30% of foodborne listeriosis infections in high-risk individuals may be fatal. Responsible for an estimated 1,600 illnesses and 260 deaths in the United States annually, listeriosis ranks third in total number of deaths among foodborne bacterial pathogens, with fatality rates exceeding even Salmonella spp. and Clostridium botulinum. In the European Union, listeriosis follows an upward trend that began in 2008, causing 2,161 confirmed cases and 210 reported deaths in 2014, 16% more than in 2013. Listeriosis mortality rates are also higher in the EU than for other foodborne pathogens.

Exotoxin

An exotoxin is a toxin secreted by bacteria. 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. Exotoxins may be secreted, or, similar to endotoxins, may be released during lysis of the cell. Gram negative pathogens may secrete outer membrane vesicles containing lipopolysaccharide endotoxin and some virulence proteins in the bounding membrane along with some other toxins as intra-vesicular contents, thus adding a previously unforeseen dimension to the well-known eukaryote process of membrane vesicle trafficking, which is quite active at the host-pathogen interface.

<i>Listeria</i> Genus of bacteria

Listeria is a genus of bacteria that acts as an intracellular parasite in mammals. Until 1992, 10 species were known, each containing two subspecies. By 2020, 21 species had been identified. The genus received its current name, after the British pioneer of sterile surgery Joseph Lister, in 1940. Listeria species are Gram-positive, rod-shaped, and facultatively anaerobic, and do not produce endospores. The major human pathogen in the genus Listeria is L. monocytogenes. It is usually the causative agent of the relatively rare bacterial disease listeriosis, an infection caused by eating food contaminated with the bacteria. Listeriosis can cause serious illness in pregnant women, newborns, adults with weakened immune systems and the elderly, and may cause gastroenteritis in others who have been severely infected.

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).

Virulence factors are cellular structures, molecules and regulatory systems that enable microbial pathogens to achieve the following:

Cytolysin refers to the substance secreted by microorganisms, plants or animals that is specifically toxic to individual cells, in many cases causing their dissolution through lysis. Cytolysins that have a specific action for certain cells are named accordingly. For instance, the cytolysins responsible for the destruction of red blood cells, thereby liberating hemoglobins, are named hemolysins, and so on. Cytolysins may be involved in immunity as well as in venoms.

Pascale Cossart French bacteriologist

Pascale Cossart is a French bacteriologist who is affiliated with the Pasteur Institute of Paris. She is the foremost authority on Listeria monocytogenes, a deadly and common food-borne pathogen responsible for encephalitis, meningitis, bacteremia, gastroenteritis, and other diseases.

Hemolysin Molecule destroying the membrane of red blood cells

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 acquisition, many hemolysins produced by pathogens do not cause significant destruction of red blood cells during infection. However, hemolysins are often capable of lysing red blood cells in vitro.

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. It has been shown that the untranslated mRNA (UTR) preceding prfA, forms a secondary structure, which masks the ribosome binding region. It is thought that at 37 °C, the hairpin structure 'melts' and the SD sequence is unmasked.

Zinc-dependent phospholipase C

In molecular biology, zinc-dependent phospholipases C is a family of bacterial phospholipases C enzymes, some of which are also known as alpha toxins.

Internalins are surface proteins found on Listeria monocytogenes. They exist in two known forms, InlA and InlB. They are used by the bacteria to invade mammalian cells via cadherins transmembrane proteins and Met receptors respectively. The exact role of these proteins and their invasiveness in vivo is not completely understood. In cultured cells, InlA is necessary to facilitate Listeria entry into human epithelial cells, while InlB is necessary for Listeria internalisation in several other cell types, including hepatocytes, fibroblasts, and epithelioid cells. Internalins are mainly surface-exposed virulence factors present in a number of Gram-positive bacteria whose role ranges from recognition of cellular receptors to aid in pathogen entry to escape from autophagy.

Listeria monocytogenes non-coding RNA

Listeria monocytogenes is a gram positive bacterium and causes many food-borne infections such as Listeriosis. This bacteria is ubiquitous in the environment where it can act as either a saprophyte when free living within the environment or as a pathogen when entering a host organism. Many non-coding RNAs have been identified within the bacteria genome where several of these have been classified as novel non-coding RNAs and may contribute to pathogenesis.

The RTX toxin superfamily is a group of cytolysins and cytotoxins produced by bacteria. There are over 1000 known members with a variety of functions. The RTX family is defined by two common features: characteristic repeats in the toxin protein sequences, and extracellular secretion by the type I secretion systems (T1SS). The name RTX refers to the glycine and aspartate-rich repeats located at the C-terminus of the toxin proteins, which facilitate export by a dedicated T1SS encoded within the rtx operon.

Actin assembly-inducing protein

The Actin assembly-inducing protein (ActA) is a protein encoded and used by Listeria monocytogenes to propel itself through a mammalian host cell. ActA is a bacterial surface protein comprising a membrane-spanning region. In a mammalian cell the bacterial ActA interacts with the Arp2/3 complex and actin monomers to induce actin polymerization on the bacterial surface generating an actin comet tail. The gene encoding ActA is named actA or prtB.

The Thiol-activated Cholesterol-dependent Cytolysin(CDC) family is a member of the MACPF superfamily. Cholesterol dependent cytolysins are a family of β-barrel pore-forming exotoxins that are secreted by gram-positive bacteria. CDCs are secreted as water-soluble monomers of 50-70 kDa, that when bound to the target cell, form a circular homo-oligomeric complex containing as many as 40 monomers. Through multiple conformational changes, the β-barrel transmembrane structure is formed and inserted into the target cell membrane. The presence of cholesterol in the target membrane is required for pore formation, though the presence of cholesterol is not required by all CDCs for binding. For example, Intermedilysin secreted by Streptococcus intermedius will bind only to target membranes containing a specific protein receptor, independent of the presence of cholesterol, but cholesterol is required by intermedilysin for pore formation. While the lipid environment of cholesterol in the membrane can affect toxin binding, the exact molecular mechanism that cholesterol regulates the cytolytic activity of the CDC is not fully understood.

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Bromo adjacent homology domain containing 1

Bromo adjacent homology domain containing 1(BAHD1) is a protein that in humans is encoded by the BAHD1 gene. BAHD1 is involved in heterochromatin formation and transcriptional repression.

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Nucleomodulin

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References

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