Listeria Monocytogenes Infections

Listeria spp. are motile, flagellated, gram-positive, facultative intracellular bacilli. The major pathogenic species is Listeria monocytogenes. Listeria are part of the normal gastrointestinal flora of domestic mammals and poultry and are transmitted to humans through the ingestion of contaminated food, especially unpasteurized dairy products. Listeria can also infect the fetus in utero or neonates during vaginal birth. Healthy individuals exposed to L. monocytogenes usually do not become ill if the inoculum is small, or may develop only self-limiting gastroenteritis. Immunocompromised or elderly individuals, neonates, and pregnant women can develop invasive disease, including meningitis and bacteremia. Treatment of invasive listeriosis includes ampicillin and gentamicin.

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General Characteristics

General characteristics of Listeria species include:

  • Gram-positive bacilli
  • Motile by flagella in culture (tumbling motility at 22–28°C (71.6–82.4°F), but not at 37°C (98.6°F)
  • Motile by cell-to-cell movement in the host organism
  • Facultative intracellular anaerobes
  • Catalase positive
  • Non-spore forming
  • Can survive and grow at low temperatures (as low as 1ºC (33.8°F)), low pH, and high-salt conditions
  • Has a weak β-hemolysin, also called listeriolysin O (LLO), which is important in the pathogenesis 
Scanning electron micrograph of Listeria monocytogenes bacterium

Scanning electron micrograph of Listeria monocytogenes bacterium

Image: “2287” by Elizabeth White. License: Public Domain

Pathophysiology

Virulence factors

  • Intracellular growth protects bacteria from the humoral immune response.
  • Cell-to-cell movement of bacteria within the host allows for the spread of infection without exposing bacteria to the immune system.
  • L. monocytogenes produces several proteins that are crucial for its pathogenesis:
    • LLO, a weak β-hemolysin similar to streptolysin; produces phagosome membrane disruption, which allows its intracellular survival and escape from vacuoles.
    • Phospholipase A (PlcA) and B (PlcB) aid in the bacteria’s escape from host cell vacuoles.
    • Actin assembly-inducing protein (ActA) is responsible for intracellular motility.
    • Internalins (InlA and InlB) are invasins that mediate the bacterial invasion of host cells via cadherin transmembrane proteins and Met receptors, respectively.

Pathogenesis

  1. Exposure of a healthy individual to large amounts of L. monocytogenes or of an immunocompromised, elderly, pregnant, or neonatal individual to small amounts of L. monocytogenes
  2. Adhesin proteins facilitate the binding to host cells and internalins interact with E-cadherin on the host cell surface to promote phagocytosis of free bacteria.
  3. Listeriolysin O causes rupture of the phagolysosome → releases bacteria into the phagocytic cell’s cytoplasm → bacteria replicates
  4. ActA induces actin polymerization (“actin rockets”) → move the bacteria to the cell surface where they form filopodia projections
  5. Projections, or filopodia, are ingested by adjacent non-phagocytic epithelial cells.
  6. Bacteria become intracellular pathogens only, spreading from cell to cell without exposure to antibodies, complement, or neutrophils.
Listeria cycle of infections

(a) L. monocytogenes invades the host cell via the interaction of surface internalins InlA and InlB with the host cell surface receptors E-cadherin and Met, respectively.
(b) Listeria escapes from the phagosome via the action of the toxins LLO and phospholipase A and B (PlcA and PlcB).
(c) Listeria replicates in the cytosol and (d) propels to the cell surface via actin polymerization, (e) promoting cell-to-cell spread.
(f) Rupture of the two-membrane vacuole is also mediated by the LLO and phospholipase toxins.

Image by Lecturio.

Immune response

  • Innate immunity: 
    • Mediated by neutrophils, macrophages, cytokines, and chemokines
    • Mostly avoided due to intracellular nature and cell-to-cell spread
  • Acquired immunity
    • Mostly cell-mediated because Listeria remains intracellular
    • Killed vaccines do not provide protective immunity because they do not provoke a cell-mediated response.

Transmission and Epidemiology

Transmission

  • Ingestion of contaminated food
    • Unpasteurized dairy products (e.g., soft cheeses and raw milk)
    • Cold deli or smoked meats
  • Transplacental transmission to the fetus
  • Vaginal transmission to the neonate during birth
  • No other person-to-person or waterborne transmission occurs.
  • The incubation period after exposure to the bacteria can last 1–70 days, but symptoms usually develop within 30 days.

Risk factors

An invasive form of the disease can develop in certain populations:

  • Immunocompromised individuals
  • Elderly individuals (> 65 years of age)
  • Neonates
  • Pregnant women (increases risk 10-fold)
    • Related to the mechanisms of fetomaternal tolerance, including decreased number of circulating T cells during pregnancy
    • 70%–90% of fetuses of infected women become infected.
  • Pre-existing gastrointestinal disease (e.g., inflammatory bowel disease, Clostridioides difficile infection) may increase risk of invasive Listeria infection or exacerbate the pre-existing condition.

Epidemiology

  • L. monocytogenes is widely distributed.
    • In nature: soil, the intestinal tract of domestic mammals, rodents, and birds
    • Approximately 0.1%–5% of healthy asymptomatic adults may have positive stool cultures for L. monocytogenes.
  • Infections are mostly sporadic, but outbreaks can occur.
  • Incidence in the United States: 1,600/year (with approximately 260 deaths/year)

Clinical Presentation

Depending on the size of the inoculum and the state of the immune system of the individual, L. monocytogenes infection can present in various ways.

  • Healthy individuals usually do not become ill or may develop only self-limiting gastroenteritis. 
  • High-risk individuals can develop an invasive disease, known as listeriosis, including:
    • Bacteremia
    • Central nervous system (CNS) infection: meningitis, meningoencephalitis, brain abscess
    • Chorioamnionitis, abortion, or stillbirth in pregnant women
    • Congenital listeriosis in fetuses and neonates
Table: Listeria monocytogenes Infections
Type of clinical presentationClinical ceatures
Self-limited gastroenteritis Presents in healthy individuals < 48 hours after ingesting large inoculum in contaminated food:
  • Fever
  • Watery diarrhea
  • Headache
  • Bacteremia is rare
No treatment necessary
Bacteremia/septicemiaPresents in immunocompromised or elderly individuals:
  • Fever
  • Watery diarrhea
  • Myalgias/arthralgias
  • Headache
  • Flu-like illness
  • Nausea and/or vomiting
CNS infectionsPresents in immunocompromised or elderly individuals:
  • Meningitis
  • 5%–10% of all community-acquired meningitis cases in the United States
    • May mimic aseptic meningitis in chronically ill or older individuals
    • Presents with neck stiffness, altered consciousness, ataxia, and seizures (frequently subacutely)
    • CSF: WBC count < 1,000/µL
  • Brain abscesses are possible.
    • CSF may be normal.
    • Neurologic sequelae due to mass effect are possible.
Infection in pregnant women
  • Can cause miscarriage and stillbirth
  • CNS involvement is rare.
  • Septicemia can present as a flu-like illness and facilitates transplacental transmission.
  • Can progress to acute chorioamnionitis, with placenta showing acute intervillositis with intervillous microabscesses
Infection in fetuses/neonates (congenital listeriosis)
  • 70%–90% of fetuses become infected.
  • Mortality rate:
    • Fetuses in utero have a 50% mortality rate.
    • Live-born neonates if treated have a 20% mortality rate.
  • Early-onset form:
    • Also known as granulomatosis infantiseptica
    • Fetal infection through transplacental transmission
    • Leads to widespread miliary microabscesses and granulomas
  • Late-onset form:
    • Neonatal infection during or soon after birth
    • Presents 2–3 weeks after exposure as neonatal meningitis and septicemia

Diagnosis and Management

Diagnosis

  • Confirmation of causative agent is not needed in healthy individuals presenting with self-limiting gastroenteritis.
  • Invasive disease can be diagnosed via bacterial identification.
    • Listeria is identified through characteristic tumbling motility or growth in cold temperatures.
    • Identification can be achieved through blood or CSF culture.
  • CSF analysis will be suggestive of bacterial meningitis:
    • Elevated WBC (neutrophils)
    • Elevated protein levels
    • Decreased glucose

Management

  • Uncomplicated self-limiting gastroenteritis: no treatment
  • Invasive disease: 
    • IV ampicillin for adults 
    • IV ampicillin and gentamicin for neonates
    • IV trimethoprim-sulfamethoxazole (TMP-SMX) for penicillin-allergic patients

Prevention

  • Avoiding unpasteurized dairy products
  • Fully cooking all meats
  • Washing fresh vegetables before consumption

Differential Diagnosis

The differential diagnosis of listeriosis includes all causes of meningitis or septicemia.

Bacterial meningitisViral meningitisFungal/tuberculous (TB) meningitis
GlucoseNormal
ProteinNormal
WBC↑ Polymorphonuclear leukocytes (PMNs)↑ Lymphocytes↑↑ Lymphocytes
Opening pressureNormal↑↑
ColorTurbidClear or bloodyClear or opaque

References

  1. Riedel, S., Hobden, J.A. (2019). In Riedel, S, Morse, S.A., Mietzner, T., Miller, S. (Eds.), Jawetz, Melnick, & Adelberg’s Medical Microbiology (28th ed, pp. 199–201).
  2. Hohmann, E.L., Portnoy, D.A. (2018). In Jameson, J.L., et al. (Ed.), Harrison’s Principles of Internal Medicine (20th ed. Vol 2, pp. 1100–1102). 
  3. Gelfand, M.S. (2020). Clinical manifestations and diagnosis of Listeria monocytogenes infection. Uptodate. Retrieved November 2, 2020, from https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-listeria-monocytogenes-infection?search=listeria&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1
  4. Medawar’s paradox and immune mechanisms of fetomaternal tolerance. (2020). OBM Transplantation | Medawar’s Paradox and Immune Mechanisms of Fetomaternal Tolerance. Retrieved November 4, 2020, from https://www.lidsen.com/journals/transplantation/
  5. U.S. Department of Agriculture. FSIS best practices guidance for controlling Listeria monocytogenes (Lm) in retail delicatessens. Retrieved November 3, 2020, from https://www.fsis.usda.gov/wps/portal/fsis/topics/regulatory-compliance/compliance-guides-index/controlling-lm-retail-delicatessens
  6. Vázquez-Boland J.A., Kuhn M, Berche P, Chakraborty T, Domínguez-Bernal G, Goebel W., González-Zorn B, Wehland J, Kreft J (2001). Listeria Pathogenesis and Molecular Virulence Determinants. Clin Microbiol Rev. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC88991/

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