Virulence factors, Pathogenesis and Clinical manifestations of Listeria monocytogenes

Virulence factors of Listeria monocytogenes

1. Adhesion proteins (Ami, Fbp A, flagellin)

• Mediate bacterial binding to host cell that contribute to virulence.

2. Listeriolysin O

• A hemolytic and cytotoxic toxin that allows for survival within phagocytes.

3. Internalin

• Cell surface protein that induces phagocytosis.

4. Act A

• Induces actin polymerization on the surface of host cells, producing cellular extensions and facilitating cell-to-cell spread.

5. Siderophores

• Organisms capable of scavenging iron from human transferrin and for enhanced growth of organism.

Pathogenesis of Listeria monocytogenes

• Human infections may result if 10ˆ6–10ˆ9 pathogens enter the gastrointestinal tract after ingestion of contaminated foods such as cheese, fruit, or vegetables.
• The organism has several adhesin proteins (Ami, Fbp A, and flagellin proteins) that facilitate bacterial binding to the host cells contributing to virulence.
• L. monocytogenes enters phagocytic and nonphagocytic cells and a listerial surface protein, internalin A and B that interact with E-cadherin, a receptor on epithelial cells, promoting phagocytosis into the epithelial cells.
• After phagocytosis, the bacterium is enclosed in a phagolysosome, where the low pH activates the bacterium to produce listeriolysin O.
• This enzyme, along with two phospholipases, lyses the membrane of the phagolysosome and allows the listeriae to escape into the cytoplasm of the epithelial cell and the organisms proliferate.
• In the host cell cytoplasm, where bacterial growth occurs, ActA, another listerial surface protein, induces host cell actin polymerization, which propels them to the cell membrane.
• The ability to polymerize actin preferentially on the older pole of the listeria cell with a surface protein (ActA) subverts the host cell’s cytoskeleton and confers intracellular motility to the bacterium.
• The resulting ‘comet tail’-like structure pushes the bacterium into an adjacent mammalian cell, where it again becomes encapsulated in a vacuole.
• Pushing against the host cell membrane, they cause formation of elongated protrusions called filopods.
• These filopods are ingested by adjacent epithelial cells, macrophages, and hepatocytes, the listeriae are released, and the cycle begins again.
• L monocytogenes can move from cell to cell without being exposed to antibodies, complement, or polymorphonuclear cells.
• Iron is an important virulence factor and hence Listeria produce siderophores and are able to obtain iron from transferrin.
• If the T cell–mediated immune response of the host is inadequate, Listeria monocytogenes can multiply in hepatocytes and macrophages freely, able to reach various organs via blood – particularly the brain or uterus right through the blood–brain barrier or the placental barrier.
• Immunity to L monocytogenes is primarily cell mediated, as demonstrated by the intracellular location of infection and by the marked association of infection with conditions of impaired cell-mediated immunity such as pregnancy, advanced age, AIDS, lymphoma, and organ transplantation.
• Immunity can be transferred by sensitized lymphocytes but not by antibodies.

Clinical manifestations of Listeria monocytogenes

Infection in pregnancy

• Listeriosis in pregnancy is classified by fetal gestation at onset.
• Maternal listeriosis occurs throughout gestation, but is rare before 20 weeks of pregnancy.
• Pregnant women often have very mild symptoms (chills, fever, back pain, sore throat and headache, sometimes with conjunctivitis, diarrhoea or drowsiness), but may be asymptomatic until the delivery of an infected infant.
• Pregnant women, usually in the third trimester, may have a milder “flulike” illness that may resolve without treatment.
• Symptomatic women may have positive blood cultures. Cultures from high vaginal swabs, stool and midstream urine samples, together with pre- or postnatal antibody tests, are of little help in diagnosis.
• With the onset of fever, fetal movements are reduced, and premature labour occurs within about 1 week.
• There may be a transient fever during labour, and the amniotic fluid is often discoloured or stained with meconium.
• Culture of the amniotic fluid, placenta or high vaginal swab after delivery invariably yields a heavy growth of L. monocytogenes.
• Although the outcome of infection for the mother is invariably benign, the outcome for the infant is more variable.

Neonatal disease

• Two forms of neonatal disease have been described: (1) early-onset disease, acquired transplacentally in utero, and (2) late-onset disease, acquired at or soon after birth.
• Early-onset disease can result in abortion, stillbirth, or premature birth.
• Granulomatosis infantiseptica is a severe form of early-onset listeriosis, characterized by formation of abscesses and granulomas in multiple organs especially in the liver, spleen and lungs and a high mortality rate unless treated promptly.
• In contrast, late neonatal infection is predominantly meningitis and may be associated with hospital cross-infection acquired from an early onset neonatal case.
• Those neonates who die from infection usually do so within a few days of birth and have pneumonia, hepatosplenomegaly, petechiae, abscesses in the liver or brain, peritonitis and enterocolitis.
• In late-onset neonatal disease, the cerebrospinal fluid (CSF) protein content is almost always raised and the glucose level reduced.
• The total number of white cells is increased but the counts are variable; neutrophils usually predominate, but lymphocytes or monocytes may be the main cell type.

Adult and juvenile infection

• In adults and juveniles the main syndromes are septicaemia and central nervous system infection.
• Most cases occur in immunosuppressed patients receiving steroid or cytotoxic therapy or with malignant neoplasms.
• Autoimmune disease, diabetes, alcohol related disease and immunosuppressive treatments are all risk factors for listerial infection.
• However, about one-third of patients with meningitis and around 10% with primary bacteraemia are apparently immunocompetent.
• Listeriosis in children older than 1 month is very rare, except in those with underlying disease.

Meningitis

• Listeria monocytogenesmay cause meningitis accompanied by seizures, or rhomboencephalitis (an infection of the brain stem).
• The clinical presentation is same in all groups, but progression is more rapid in immunocompromised cases.
• A peripheral blood leucocytosis occurs, and the CSF white blood cell count is raised.
• The glucose level in CSF is low and the protein level is raised
• A very high protein concentration may be a poor prognostic indicator.
• Gram stains of the CSF are often negative.
• In the rare cases of encephalitis, cerebritis or cerebral abscesses, the CSF may be normal, but the white blood cell count is often raised mildly and the protein level is slightly increased, with a low glucose concentration.
• The Gram film and culture are usually negative.
• Blood cultures are the main source of the organism in many of these patients.

Bacteraemia

• Primary bacteraemia is more common in men than in women, and occurs most often in patients >60 years of age as well as those with haematological malignancy or a renal transplant.
• Listerial bacteraemia is associated more often with gastrointestinal symptoms, particularly those with gastric malignancies, and treatment to reduce stomach acid secretion.

Gastroenteritis

• Healthy persons exposed to L monocytogenes in food may not become ill or may develop a mild, self-limiting febrile gastroenteritis lasting 1–3 days.
• This develops after an incubation period of 6–48 hours.
• Symptoms include fever, chills, headache, myalgias, abdominal pain, and diarrhea.
• Large numbers of L. monocytogenes are present in the stool, and a few patients develop serious systemic infection.
• The ability to cause gastroenteritis may be specific to certain strains.

Other infections

• Rarer manifestations of listeriosis include arthritis, hepatitis, endophthalmitis, pneumonia, endocarditis, cutaneous lesions and peritonitis in patients on continuous ambulatory peritoneal dialysis.