Listeria monocytogenes
Encyclopedia
Listeria monocytogenes, a facultative anaerobe
, intracellular bacterium, is the causative agent of listeriosis. It is one of the most virulent
foodborne pathogens, with 20 to 30 percent of clinical infections resulting in death. Responsible for approximately 2,500 illnesses and 500 deaths in the United States (U.S.) annually, listeriosis is the leading cause of death among foodborne bacterial pathogens, with fatality rates exceeding even Salmonella
and Clostridium botulinum
.
L. monocytogenes is a Gram-positive
bacterium, in the division Firmicutes
, named for Joseph Lister
. Motile
via flagella at 30°C and below, but usually not at 37°C, L. monocytogenes can instead move within eukaryotic
cells by explosive polymerization
of actin
filaments (known as comet tails or actin rockets).
Studies suggest up to 10% of human gastrointestinal tract
s may be colonized by L. monocytogenes.
Nevertheless, clinical diseases due to L. monocytogenes are more frequently recognized by veterinarian
s, especially as meningoencephalitis
in ruminant
s. See: listeriosis in animals.
Due to its frequent pathogenicity
, causing meningitis in newborns (acquired transvaginally), pregnant mothers are often advised not to eat soft cheeses such as Brie, Camembert
, feta, and queso blanco fresco
, which may be contaminated with and permit growth of L. monocytogenes. It is the third-most-common cause of meningitis in newborns.
More recently, L. monocytogenes has been used as the model organism
to illustrate the pathobiotechnology
concept.
The genus Listeria belongs to the class, Bacilli, and the order, Bacillales, which also includes Bacillus and Staphylococcus. The genus Listeria includes seven different species (L. monocytogenes, L. ivanovii, L. innocua, L. welshimeri, L. seeligeri, L. grayi, and L. murrayi). Both L. ivanovii and L. monocytogenes are pathogenic in mice, but only L. monocytogenes is consistently associated with human illness. There are 13 serotypes of L. monocytogenes that can cause disease, but more than 90 percent of human isolates belong to only three serotypes: 1/2a, 1/2b, and 4b. L. monocytogenes serotype 4b strains are responsible for 33 to 50 percent of sporadic human cases worldwide and for all major foodborne outbreaks in Europe and North America since the 1980s.
Murray referred to the organism as Bacterium monocytogenes before J.H. Harvey Pirie changed the genus name to Listeria in 1940. Although clinical descriptions of L. monocytogenes infection in both animals and humans were published in the 1920s, not until 1952 in East Germany was it recognized as a significant cause of neonatal sepsis
and meningitis
. Listeriosis in adults would later be associated with patients living with compromised immune systems, such as individuals taking immunosuppressant drugs
and corticosteroids for malignancies or organ transplants, and those with HIV infection.
Not until 1981, however, was L. monocytogenes identified as a cause of foodborne illness. An outbreak of listeriosis in Halifax
, Nova Scotia
involving 41 cases and 18 deaths, mostly in pregnant women and neonates, was epidemiologically linked to the consumption of coleslaw containing cabbage that had been treated with L. monocytogenes-contaminated raw sheep manure. Since then, a number of cases of foodborne listeriosis have been reported, and L. monocytogenes is now widely recognized as an important hazard in the food industry.
by L. monocytogenes causes the disease listeriosis. When the infection is not invasive, any illness as a consequence of infection is termed febrile gastroenteritis. The manifestations of listeriosis include septicemia, meningitis
(or meningoencephalitis
), encephalitis
, corneal ulcer, pneumonia, and intrauterine
or cervical
infections in pregnant women, which may result in spontaneous abortion
(second to third trimester) or stillbirth
. Surviving neonates of fetomaternal listeriosis may suffer granulomatosis infantiseptica - pyogenic granulomas distributed over the whole body, and may suffer from physical retardation. Influenza
-like symptoms, including persistent fever, usually precede the onset of the aforementioned disorders. Gastrointestinal symptoms, such as nausea, vomiting, and diarrhea
, may precede more serious forms of listeriosis or may be the only symptoms expressed. Gastrointestinal symptoms were epidemiologically associated with use of antacid
s or cimetidine
. The onset time to serious forms of listeriosis is unknown, but may range from a few days to three weeks. The onset time to gastrointestinal symptoms is unknown but probably exceeds 12 hours. An early study suggested that L. monocytogenes is unique among Gram-positive
bacteria in that it might possess lipopolysaccharide
, which serves as an endotoxin
. Later it was found to not be a true endotoxin. Listeria cell walls consistently contain lipoteichoic acids, in which a glycolipid moiety, such as a galactosyl-glucosyl-diglyceride, is covalently linked to the terminal phosphomonoester of the teichoic acid. This lipid region anchors the polymer chain to the cytoplasmic membrane. These lipoteichoic acids resemble the lipopolysaccharides of Gram-negative bacteria in both structure and function, being the only amphipathic polymers at the cell surface.
The infective dose of L. monocytogenes varies with the strain and with the susceptibility of the victim. From cases contracted through raw or supposedly pasteurized milk, one may safely assume that, in susceptible persons, fewer than 1,000 total organisms may cause disease. L. monocytogenes may invade the gastrointestinal epithelium. Once the bacterium enters the host's monocyte
s, macrophage
s, or polymorphonuclear leukocytes, it becomes blood-borne (septicemic) and can grow. Its presence intracellularly in phagocytic cells also permits access to the brain and probably transplacental migration to the fetus in pregnant women. The pathogenesis of L. monocytogenes centers on its ability to survive and multiply in phagocytic host cells. It seems that Listeria originally evolved to invade membranes of the intestines, as an intracellular infection, and developed a chemical mechanism to do so. This involves a bacterial protein " internalin" which attaches to a protein on the intestinal cell membrane " cadherin." These adhesion molecules are also to be found in two other unusually tough barriers in humans - the blood brain barrier and the feto - placental barrier, and this may explain the apparent affinity that Listeria has for causing meningitis and affecting babies in-utero.
, depending on its environment. When this bacterium is present within a host organism, quorum sensing
causes the up regulation of several virulence
genes. Depending on the location of the bacterium within the host organism, different activators up regulate the virulence genes. SigB, an alternative sigma factor
, up regulates Vir genes in the intestines, whereas PrfA
up regulates gene expression when the bacterium is present in blood. Little is known about how this bacterium switches between acting as a saprophyte and a pathogen; however, several noncoding RNAs are thought to be required to induce this change.
may reach 70%, from septicemia 50%, and from perinatal/neonatal infections greater than 80%. In infections during pregnancy, the mother usually survives. Reports of successful treatment with parenteral penicillin
or ampicillin
exist. Trimethoprim-sulfamethoxazole has been shown effective in patients allergic to penicillin.
Bacteriophage treatments have been developed by several companies. EBI Food Safety and Intralytix both have products suitable for treatment of the bacterium. The U.S. Food and Drug Administration (FDA) approved a cocktail of six bacteriophage
s from Intralytix, and a one type phage product from EBI Food Safety designed to kill L. monocytogenes. Uses would potentially include spraying it on fruits and ready-to-eat meat such as sliced ham and turkey.
. Current transfection
efficiency remains poor. One example of the successful use of L. monocytogenes in in vitro transfer technologies is in the delivery of gene therapies for cystic fibrosis cases.
, ADXS11-001, is under development as a possible treatment for cervical carcinoma.
The methods for analysis of food are complex and time-consuming. The present U.S. FDA method, revised in September 1990, requires 24 and 48 hours of enrichment, followed by a variety of other tests. Total time to identification takes from five to seven days, but the announcement of specific nonradiolabelled DNA probes should soon allow a simpler and faster confirmation of suspect isolates.
Recombinant DNA technology may even permit two- to three-day positive analysis in the future. Currently, the FDA is collaborating in adapting its methodology to quantitate very low numbers of the organisms in foods.
, both domesticated and feral, as well as in at least 17 species of birds and possibly in some species of fish
and shellfish
. Laboratories can isolate L. monocytogenes from soil
, silage
, and other environmental sources. L. monocytogenes is quite hardy and resists the deleterious effects of freezing, drying, and heat remarkably well for a bacterium that does not form spores. Most L. monocytogenes are pathogenic to some degree.
, pasteurized fluid milk, cheese
s (particularly soft-ripened varieties), ice cream
, raw vegetables, fermented raw-meat sausage
s, raw and cooked poultry
, raw meats (of all types), and raw and smoked fish
. Its ability to grow at temperatures as low as 0°C permits multiplication in refrigerated foods. At refrigeration temperature, such as 4°C, the amount of ferric iron can affect the growth of L. monocytogenes.
or Met. This binding activates certain Rho-GTPases, which subsequently bind and stabilize Wiskott Aldrich syndrome protein (WAsp). WAsp can then bind the Arp2/3 complex
and serve as an actin
nucleation point. Subsequent actin polymerization extends the cell membrane around the bacterium, eventually engulfing it. The net effect of internalin binding is to exploit the junction-forming apparatus of the host into internalizing the bacterium. L. monocytogenes can also invade phagocytic cells (e.g., macrophages), but requires only internalins for invasion of nonphagocytic cells.
Following internalization, the bacterium must escape from the vacuole/phagosome before fusion with a lysosome
can occur. Three main virulence factors that allow the bacterium to escape are listeriolysin O (LLO - encoded by hly) phospholipase A (encoded by plcA) and phospholipase B
(plcB). Secretion of LLO and PlcB disrupts the vacuolar membrane and allows the bacterium to escape into the cytoplasm, where it may proliferate.
Once in the cytoplasm, L. monocytogenes exploits host actin
for the second time. ActA proteins
associated with the old bacterial cell pole (being a bacillus, L. monocytogenes septates in the middle of the cell and thus has one new pole and one old pole) are capable of binding the Arp2/3 complex
, thereby inducing actin nucleation at a specific area of the bacterial cell surface. Actin polymerization then propels the bacterium unidirectionally into the host cell membrane. The protrusion that is formed may then be internalized by a neighboring cell, forming a double-membrane vacuole from which the bacterium must escape using LLO and PlcB. This mode of direct cell-to-cell spread involves a cellular mechanism known as paracytophagy
.
Facultative anaerobic organism
A facultative anaerobic organism is an organism, usually a bacterium, that makes ATP by aerobic respiration if oxygen is present but is also capable of switching to fermentation...
, intracellular bacterium, is the causative agent of listeriosis. It is one of the most virulent
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...
foodborne pathogens, with 20 to 30 percent of clinical infections resulting in death. Responsible for approximately 2,500 illnesses and 500 deaths in the United States (U.S.) annually, listeriosis is the leading cause of death among foodborne bacterial pathogens, with fatality rates exceeding even Salmonella
Salmonella
Salmonella is a genus of rod-shaped, Gram-negative, non-spore-forming, predominantly motile enterobacteria with diameters around 0.7 to 1.5 µm, lengths from 2 to 5 µm, and flagella which grade in all directions . They are chemoorganotrophs, obtaining their energy from oxidation and reduction...
and Clostridium botulinum
Clostridium botulinum
Clostridium botulinum is a Gram-positive, rod-shaped bacterium that produces several toxins. The best known are its neurotoxins, subdivided in types A-G, that cause the flaccid muscular paralysis seen in botulism. It is also the main paralytic agent in botox. C. botulinum is an anaerobic...
.
L. monocytogenes is a Gram-positive
Gram-positive
Gram-positive bacteria are those that are stained dark blue or violet by Gram staining. This is in contrast to Gram-negative bacteria, which cannot retain the crystal violet stain, instead taking up the counterstain and appearing red or pink...
bacterium, in the division Firmicutes
Firmicutes
The Firmicutes are a phylum of bacteria, most of which have Gram-positive cell wall structure. A few, however, such as Megasphaera, Pectinatus, Selenomonas and Zymophilus, have a porous pseudo-outer-membrane that causes them to stain Gram-negative...
, named for Joseph Lister
Joseph Lister, 1st Baron Lister
Joseph Lister, 1st Baron Lister OM, FRS, PC , known as Sir Joseph Lister, Bt., between 1883 and 1897, was a British surgeon and a pioneer of antiseptic surgery, who promoted the idea of sterile surgery while working at the Glasgow Royal Infirmary...
. Motile
Motility
Motility is a biological term which refers to the ability to move spontaneously and actively, consuming energy in the process. Most animals are motile but the term applies to single-celled and simple multicellular organisms, as well as to some mechanisms of fluid flow in multicellular organs, in...
via flagella at 30°C and below, but usually not at 37°C, L. monocytogenes can instead move within eukaryotic
Eukaryote
A eukaryote is an organism whose cells contain complex structures enclosed within membranes. Eukaryotes may more formally be referred to as the taxon Eukarya or Eukaryota. The defining membrane-bound structure that sets eukaryotic cells apart from prokaryotic cells is the nucleus, or nuclear...
cells by explosive polymerization
Polymerization
In polymer chemistry, polymerization is a process of reacting monomer molecules together in a chemical reaction to form three-dimensional networks or polymer chains...
of actin
Actin
Actin is a globular, roughly 42-kDa moonlighting protein found in all eukaryotic cells where it may be present at concentrations of over 100 μM. It is also one of the most highly-conserved proteins, differing by no more than 20% in species as diverse as algae and humans...
filaments (known as comet tails or actin rockets).
Studies suggest up to 10% of human gastrointestinal tract
Gastrointestinal tract
The human gastrointestinal tract refers to the stomach and intestine, and sometimes to all the structures from the mouth to the anus. ....
s may be colonized by L. monocytogenes.
Nevertheless, clinical diseases due to L. monocytogenes are more frequently recognized by veterinarian
Veterinarian
A veterinary physician, colloquially called a vet, shortened from veterinarian or veterinary surgeon , is a professional who treats disease, disorder and injury in animals....
s, especially as meningoencephalitis
Encephalitis
Encephalitis is an acute inflammation of the brain. Encephalitis with meningitis is known as meningoencephalitis. Symptoms include headache, fever, confusion, drowsiness, and fatigue...
in ruminant
Ruminant
A ruminant is a mammal of the order Artiodactyla that digests plant-based food by initially softening it within the animal's first compartment of the stomach, principally through bacterial actions, then regurgitating the semi-digested mass, now known as cud, and chewing it again...
s. See: listeriosis in animals.
Due to its frequent pathogenicity
Pathogenicity
Pathogenicity is the ability of a pathogen to produce an infectious disease in an organism.It is often used interchangeably with the term "virulence", although virulence is used more specifically to describe the relative degree of damage done by a pathogen, or the degree of pathogenicity caused by...
, causing meningitis in newborns (acquired transvaginally), pregnant mothers are often advised not to eat soft cheeses such as Brie, Camembert
Camembert (cheese)
Camembert is a soft, creamy, surface-ripened cow's milk cheese. It was first made in the late 18th century in Normandy in northern France.-Production:...
, feta, and queso blanco fresco
Queso blanco
Queso blanco, along with other similar cheeses including queso fresco, is a creamy, soft, and mild unaged white cheese that originated in Spain and spread to Mexico and other American countries...
, which may be contaminated with and permit growth of L. monocytogenes. It is the third-most-common cause of meningitis in newborns.
More recently, L. monocytogenes has been used as the model organism
Model organism
A model organism is a non-human species that is extensively studied to understand particular biological phenomena, with the expectation that discoveries made in the organism model will provide insight into the workings of other organisms. Model organisms are in vivo models and are widely used to...
to illustrate the pathobiotechnology
Patho-biotechnology
Patho-biotechnology , coined by Roy Sleator and Colin Hill , describes the exploitation of pathogenic stress survival factors in biotechnology, medicine and food....
concept.
Classification
L. monocytogenes is a Gram-positive, nonspore-forming, motile, facultatively anaerobic, rod-shaped bacterium. It is catalase-positive and oxidase-negative, and expresses a beta hemolysin, which causes destruction of red blood cells. This bacterium exhibits characteristic tumbling motility when viewed with light microscopy. Although L. monocytogenes is actively motile by means of peritrichous flagella at room temperature (20−25°C), the organism does not synthesize flagella at body temperatures (37°C).The genus Listeria belongs to the class, Bacilli, and the order, Bacillales, which also includes Bacillus and Staphylococcus. The genus Listeria includes seven different species (L. monocytogenes, L. ivanovii, L. innocua, L. welshimeri, L. seeligeri, L. grayi, and L. murrayi). Both L. ivanovii and L. monocytogenes are pathogenic in mice, but only L. monocytogenes is consistently associated with human illness. There are 13 serotypes of L. monocytogenes that can cause disease, but more than 90 percent of human isolates belong to only three serotypes: 1/2a, 1/2b, and 4b. L. monocytogenes serotype 4b strains are responsible for 33 to 50 percent of sporadic human cases worldwide and for all major foodborne outbreaks in Europe and North America since the 1980s.
History
L. monocytogenes was first described by E.G.D. Murray in 1926 based on six cases of sudden death in young rabbits.Murray referred to the organism as Bacterium monocytogenes before J.H. Harvey Pirie changed the genus name to Listeria in 1940. Although clinical descriptions of L. monocytogenes infection in both animals and humans were published in the 1920s, not until 1952 in East Germany was it recognized as a significant cause of neonatal sepsis
Sepsis
Sepsis is a potentially deadly medical condition that is characterized by a whole-body inflammatory state and the presence of a known or suspected infection. The body may develop this inflammatory response by the immune system to microbes in the blood, urine, lungs, skin, or other tissues...
and meningitis
Meningitis
Meningitis is inflammation of the protective membranes covering the brain and spinal cord, known collectively as the meninges. The inflammation may be caused by infection with viruses, bacteria, or other microorganisms, and less commonly by certain drugs...
. Listeriosis in adults would later be associated with patients living with compromised immune systems, such as individuals taking immunosuppressant drugs
Immunosuppressive drug
Immunosuppressive drugs or immunosuppressive agents are drugs that inhibit or prevent activity of the immune system. They are used in immunosuppressive therapy to:...
and corticosteroids for malignancies or organ transplants, and those with HIV infection.
Not until 1981, however, was L. monocytogenes identified as a cause of foodborne illness. An outbreak of listeriosis in Halifax
City of Halifax
Halifax is a city in Canada, which was the capital of the province of Nova Scotia and shire town of Halifax County. It was the largest city in Atlantic Canada until it was amalgamated into Halifax Regional Municipality in 1996...
, Nova Scotia
Nova Scotia
Nova Scotia is one of Canada's three Maritime provinces and is the most populous province in Atlantic Canada. The name of the province is Latin for "New Scotland," but "Nova Scotia" is the recognized, English-language name of the province. The provincial capital is Halifax. Nova Scotia is the...
involving 41 cases and 18 deaths, mostly in pregnant women and neonates, was epidemiologically linked to the consumption of coleslaw containing cabbage that had been treated with L. monocytogenes-contaminated raw sheep manure. Since then, a number of cases of foodborne listeriosis have been reported, and L. monocytogenes is now widely recognized as an important hazard in the food industry.
Pathogenesis
Invasive infectionInfection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
by L. monocytogenes causes the disease listeriosis. When the infection is not invasive, any illness as a consequence of infection is termed febrile gastroenteritis. The manifestations of listeriosis include septicemia, meningitis
Meningitis
Meningitis is inflammation of the protective membranes covering the brain and spinal cord, known collectively as the meninges. The inflammation may be caused by infection with viruses, bacteria, or other microorganisms, and less commonly by certain drugs...
(or meningoencephalitis
Meningoencephalitis
Meningoencephalitis is a medical condition that simultaneously resembles both meningitis, which is an infection or inflammation of the meninges, and encephalitis, which is an infection or inflammation of the brain.-Causes:...
), encephalitis
Encephalitis
Encephalitis is an acute inflammation of the brain. Encephalitis with meningitis is known as meningoencephalitis. Symptoms include headache, fever, confusion, drowsiness, and fatigue...
, corneal ulcer, pneumonia, and intrauterine
Uterus
The uterus or womb is a major female hormone-responsive reproductive sex organ of most mammals including humans. One end, the cervix, opens into the vagina, while the other is connected to one or both fallopian tubes, depending on the species...
or cervical
Cervix
The cervix is the lower, narrow portion of the uterus where it joins with the top end of the vagina. It is cylindrical or conical in shape and protrudes through the upper anterior vaginal wall...
infections in pregnant women, which may result in spontaneous abortion
Miscarriage
Miscarriage or spontaneous abortion is the spontaneous end of a pregnancy at a stage where the embryo or fetus is incapable of surviving independently, generally defined in humans at prior to 20 weeks of gestation...
(second to third trimester) or stillbirth
Stillbirth
A stillbirth occurs when a fetus has died in the uterus. The Australian definition specifies that fetal death is termed a stillbirth after 20 weeks gestation or the fetus weighs more than . Once the fetus has died the mother still has contractions and remains undelivered. The term is often used in...
. Surviving neonates of fetomaternal listeriosis may suffer granulomatosis infantiseptica - pyogenic granulomas distributed over the whole body, and may suffer from physical retardation. Influenza
Influenza
Influenza, commonly referred to as the flu, is an infectious disease caused by RNA viruses of the family Orthomyxoviridae , that affects birds and mammals...
-like symptoms, including persistent fever, usually precede the onset of the aforementioned disorders. Gastrointestinal symptoms, such as nausea, vomiting, and diarrhea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
, may precede more serious forms of listeriosis or may be the only symptoms expressed. Gastrointestinal symptoms were epidemiologically associated with use of antacid
Antacid
An antacid is a substance which neutralizes stomach acidity.-Mechanism of action:Antacids perform a neutralization reaction, increasing the pH to reduce acidity in the stomach. When gastric hydrochloric acid reaches the nerves in the gastrointestinal mucosa, they signal pain to the central nervous...
s or cimetidine
Cimetidine
Cimetidine INN is a histamine H2-receptor antagonist that inhibits the production of acid in the stomach. It is largely used in the treatment of heartburn and peptic ulcers. It is marketed by GlaxoSmithKline under the trade name Tagamet...
. The onset time to serious forms of listeriosis is unknown, but may range from a few days to three weeks. The onset time to gastrointestinal symptoms is unknown but probably exceeds 12 hours. An early study suggested that L. monocytogenes is unique among Gram-positive
Gram-positive
Gram-positive bacteria are those that are stained dark blue or violet by Gram staining. This is in contrast to Gram-negative bacteria, which cannot retain the crystal violet stain, instead taking up the counterstain and appearing red or pink...
bacteria in that it might possess lipopolysaccharide
Lipopolysaccharide
Lipopolysaccharides , also known as lipoglycans, are large molecules consisting of a lipid and a polysaccharide joined by a covalent bond; they are found in the outer membrane of Gram-negative bacteria, act as endotoxins and elicit strong immune responses in animals.-Functions:LPS is the major...
, which serves as an endotoxin
Endotoxin
Endotoxins are toxins associated with some Gram-negative bacteria. An "endotoxin" is a toxin that is a structural molecule of the bacteria that is recognized by the immune system.-Gram negative:...
. Later it was found to not be a true endotoxin. Listeria cell walls consistently contain lipoteichoic acids, in which a glycolipid moiety, such as a galactosyl-glucosyl-diglyceride, is covalently linked to the terminal phosphomonoester of the teichoic acid. This lipid region anchors the polymer chain to the cytoplasmic membrane. These lipoteichoic acids resemble the lipopolysaccharides of Gram-negative bacteria in both structure and function, being the only amphipathic polymers at the cell surface.
The infective dose of L. monocytogenes varies with the strain and with the susceptibility of the victim. From cases contracted through raw or supposedly pasteurized milk, one may safely assume that, in susceptible persons, fewer than 1,000 total organisms may cause disease. L. monocytogenes may invade the gastrointestinal epithelium. Once the bacterium enters the host's monocyte
Monocyte
Monocytes are a type of white blood cell and are part of the innate immune system of vertebrates including all mammals , birds, reptiles, and fish. Monocytes play multiple roles in immune function...
s, macrophage
Macrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...
s, or polymorphonuclear leukocytes, it becomes blood-borne (septicemic) and can grow. Its presence intracellularly in phagocytic cells also permits access to the brain and probably transplacental migration to the fetus in pregnant women. The pathogenesis of L. monocytogenes centers on its ability to survive and multiply in phagocytic host cells. It seems that Listeria originally evolved to invade membranes of the intestines, as an intracellular infection, and developed a chemical mechanism to do so. This involves a bacterial protein " internalin" which attaches to a protein on the intestinal cell membrane " cadherin." These adhesion molecules are also to be found in two other unusually tough barriers in humans - the blood brain barrier and the feto - placental barrier, and this may explain the apparent affinity that Listeria has for causing meningitis and affecting babies in-utero.
Regulation of pathogenesis
L. monocytogenes can act as a saprophyte or a pathogenPathogen
A pathogen gignomai "I give birth to") or infectious agent — colloquially, a germ — is a microbe or microorganism such as a virus, bacterium, prion, or fungus that causes disease in its animal or plant host...
, depending on its environment. When this bacterium is present within a host organism, quorum sensing
Quorum sensing
Quorum sensing is a system of stimulus and response correlated to population density. Many species of bacteria use quorum sensing to coordinate gene expression according to the density of their local population. In similar fashion, some social insects use quorum sensing to determine where to nest...
causes the up regulation of several 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...
genes. Depending on the location of the bacterium within the host organism, different activators up regulate the virulence genes. SigB, an alternative sigma factor
Sigma factor
A sigma factor is a bacterial transcription initiation factor that enables specific binding of RNA polymerase to gene promoters. Different sigma factors are activated in response to different environmental conditions...
, up regulates Vir genes in the intestines, whereas PrfA
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...
up regulates gene expression when the bacterium is present in blood. Little is known about how this bacterium switches between acting as a saprophyte and a pathogen; however, several noncoding RNAs are thought to be required to induce this change.
Pathogenicity of lineages
L. monocytogenes has three distinct lineages, with differing evolutionary histories and pathogenic potentials. Lineage I strains contain the majority of human clinical isolates and all human epidemic clones, but are underrepresented in animal clinical isolates. Lineage II strains are overrepresented in animal cases and underrepresented in human clinical cases, and are more prevalent in environmental and food samples. Lineage III isolates are very rare, but significantly more common in animal than human isolates.Treatment
When listeric meningitis occurs, the overall mortalityDeath
Death is the permanent termination of the biological functions that sustain a living organism. Phenomena which commonly bring about death include old age, predation, malnutrition, disease, and accidents or trauma resulting in terminal injury....
may reach 70%, from septicemia 50%, and from perinatal/neonatal infections greater than 80%. In infections during pregnancy, the mother usually survives. Reports of successful treatment with parenteral penicillin
Penicillin
Penicillin is a group of antibiotics derived from Penicillium fungi. They include penicillin G, procaine penicillin, benzathine penicillin, and penicillin V....
or ampicillin
Ampicillin
Ampicillin is a beta-lactam antibiotic that has been used extensively to treat bacterial infections since 1961. Until the introduction of ampicillin by the British company Beecham, penicillin therapies had only been effective against Gram-positive organisms such as staphylococci and streptococci...
exist. Trimethoprim-sulfamethoxazole has been shown effective in patients allergic to penicillin.
Bacteriophage treatments have been developed by several companies. EBI Food Safety and Intralytix both have products suitable for treatment of the bacterium. The U.S. Food and Drug Administration (FDA) approved a cocktail of six bacteriophage
Bacteriophage
A bacteriophage is any one of a number of viruses that infect bacteria. They do this by injecting genetic material, which they carry enclosed in an outer protein capsid...
s from Intralytix, and a one type phage product from EBI Food Safety designed to kill L. monocytogenes. Uses would potentially include spraying it on fruits and ready-to-eat meat such as sliced ham and turkey.
Use as a transfection vector
Because L. monocytogenes is an intracellular parasite, some studies have used this bacterium as a vector to deliver genes in vitroIn vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
. Current transfection
Transfection
Transfection is the process of deliberately introducing nucleic acids into cells. The term is used notably for non-viral methods in eukaryotic cells...
efficiency remains poor. One example of the successful use of L. monocytogenes in in vitro transfer technologies is in the delivery of gene therapies for cystic fibrosis cases.
Cancer vaccine
A live attenuated L. monocytogenes cancer vaccineCancer vaccine
The term cancer vaccine refers to a vaccine that either prevents infections with cancer-causing viruses, treats existing cancer or prevents the development of cancer in certain high risk individuals...
, ADXS11-001, is under development as a possible treatment for cervical carcinoma.
Detection
Recombinant DNA technology may even permit two- to three-day positive analysis in the future. Currently, the FDA is collaborating in adapting its methodology to quantitate very low numbers of the organisms in foods.
Epidemiology
Researchers have found L. monocytogenes in at least 37 mammalian speciesMammal
Mammals are members of a class of air-breathing vertebrate animals characterised by the possession of endothermy, hair, three middle ear bones, and mammary glands functional in mothers with young...
, both domesticated and feral, as well as in at least 17 species of birds and possibly in some species of fish
Fish
Fish are a paraphyletic group of organisms that consist of all gill-bearing aquatic vertebrate animals that lack limbs with digits. Included in this definition are the living hagfish, lampreys, and cartilaginous and bony fish, as well as various extinct related groups...
and shellfish
Shellfish
Shellfish is a culinary and fisheries term for exoskeleton-bearing aquatic invertebrates used as food, including various species of molluscs, crustaceans, and echinoderms. Although most kinds of shellfish are harvested from saltwater environments, some kinds are found only in freshwater...
. Laboratories can isolate L. monocytogenes from soil
Soil
Soil is a natural body consisting of layers of mineral constituents of variable thicknesses, which differ from the parent materials in their morphological, physical, chemical, and mineralogical characteristics...
, silage
Silage
Silage is fermented, high-moisture fodder that can be fed to ruminants or used as a biofuel feedstock for anaerobic digesters. It is fermented and stored in a process called ensiling or silaging, and is usually made from grass crops, including corn , sorghum or other cereals, using the entire...
, and other environmental sources. L. monocytogenes is quite hardy and resists the deleterious effects of freezing, drying, and heat remarkably well for a bacterium that does not form spores. Most L. monocytogenes are pathogenic to some degree.
Routes of infection
L. monocytogenes has been associated with such foods as raw milkMilk
Milk is a white liquid produced by the mammary glands of mammals. It is the primary source of nutrition for young mammals before they are able to digest other types of food. Early-lactation milk contains colostrum, which carries the mother's antibodies to the baby and can reduce the risk of many...
, pasteurized fluid milk, cheese
Cheese
Cheese is a generic term for a diverse group of milk-based food products. Cheese is produced throughout the world in wide-ranging flavors, textures, and forms....
s (particularly soft-ripened varieties), ice cream
Ice cream
Ice cream is a frozen dessert usually made from dairy products, such as milk and cream, and often combined with fruits or other ingredients and flavours. Most varieties contain sugar, although some are made with other sweeteners...
, raw vegetables, fermented raw-meat sausage
Sausage
A sausage is a food usually made from ground meat , mixed with salt, herbs, and other spices, although vegetarian sausages are available. The word sausage is derived from Old French saussiche, from the Latin word salsus, meaning salted.Typically, a sausage is formed in a casing traditionally made...
s, raw and cooked poultry
Poultry
Poultry are domesticated birds kept by humans for the purpose of producing eggs, meat, and/or feathers. These most typically are members of the superorder Galloanserae , especially the order Galliformes and the family Anatidae , commonly known as "waterfowl"...
, raw meats (of all types), and raw and smoked fish
Fish
Fish are a paraphyletic group of organisms that consist of all gill-bearing aquatic vertebrate animals that lack limbs with digits. Included in this definition are the living hagfish, lampreys, and cartilaginous and bony fish, as well as various extinct related groups...
. Its ability to grow at temperatures as low as 0°C permits multiplication in refrigerated foods. At refrigeration temperature, such as 4°C, the amount of ferric iron can affect the growth of L. monocytogenes.
Infectious cycle
The primary site of infection is the intestinal epithelium, where the bacteria invade nonphagocytic cells via the "zipper" mechanism. Uptake is stimulated by the binding of listerial internalins (Inl) to host cell adhesion factors, such as E-cadherinCadherin
Cadherins are a class of type-1 transmembrane proteins. They play important roles in cell adhesion, ensuring that cells within tissues are bound together. They are dependent on calcium ions to function, hence their name.The cadherin superfamily includes cadherins, protocadherins, desmogleins, and...
or Met. This binding activates certain Rho-GTPases, which subsequently bind and stabilize Wiskott Aldrich syndrome protein (WAsp). WAsp can then bind the Arp2/3 complex
Arp2/3 complex
Arp2/3 complex is a seven-subunit protein that plays a major role in the regulation of the actin cytoskeleton. It is a major component of the actin cytoskeleton and is found in most in actin cytoskeleton-containing eukaryotic cells....
and serve as an actin
Actin
Actin is a globular, roughly 42-kDa moonlighting protein found in all eukaryotic cells where it may be present at concentrations of over 100 μM. It is also one of the most highly-conserved proteins, differing by no more than 20% in species as diverse as algae and humans...
nucleation point. Subsequent actin polymerization extends the cell membrane around the bacterium, eventually engulfing it. The net effect of internalin binding is to exploit the junction-forming apparatus of the host into internalizing the bacterium. L. monocytogenes can also invade phagocytic cells (e.g., macrophages), but requires only internalins for invasion of nonphagocytic cells.
Following internalization, the bacterium must escape from the vacuole/phagosome before fusion with a lysosome
Lysosome
thumb|350px|Schematic of typical animal cell, showing subcellular components. [[Organelle]]s: [[nucleoli]] [[cell nucleus|nucleus]] [[ribosomes]] [[vesicle |vesicle]] rough [[endoplasmic reticulum]]...
can occur. Three main virulence factors that allow the bacterium to escape are listeriolysin O (LLO - encoded by hly) phospholipase A (encoded by plcA) and phospholipase B
Phospholipase B
Phospholipase B is an enzyme with a combination of both PLA1 and PLA2 activities; that is, it can cleave acyl chains from both the sn-1 and sn-2 positions of a phospholipid. In general, it acts on lysolecithin ....
(plcB). Secretion of LLO and PlcB disrupts the vacuolar membrane and allows the bacterium to escape into the cytoplasm, where it may proliferate.
Once in the cytoplasm, L. monocytogenes exploits host actin
Actin
Actin is a globular, roughly 42-kDa moonlighting protein found in all eukaryotic cells where it may be present at concentrations of over 100 μM. It is also one of the most highly-conserved proteins, differing by no more than 20% in species as diverse as algae and humans...
for the second time. ActA proteins
Actin assembly-inducing protein
The Actin assembly-inducing protein 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...
associated with the old bacterial cell pole (being a bacillus, L. monocytogenes septates in the middle of the cell and thus has one new pole and one old pole) are capable of binding the Arp2/3 complex
Arp2/3 complex
Arp2/3 complex is a seven-subunit protein that plays a major role in the regulation of the actin cytoskeleton. It is a major component of the actin cytoskeleton and is found in most in actin cytoskeleton-containing eukaryotic cells....
, thereby inducing actin nucleation at a specific area of the bacterial cell surface. Actin polymerization then propels the bacterium unidirectionally into the host cell membrane. The protrusion that is formed may then be internalized by a neighboring cell, forming a double-membrane vacuole from which the bacterium must escape using LLO and PlcB. This mode of direct cell-to-cell spread involves a cellular mechanism known as paracytophagy
Paracytophagy
Paracytophagy is the cellular process whereby a cell engulfs a protrusion which extends from a neighboring cell. This protrusion may contain material which is actively transferred between the cells...
.