Human Listeriosis.

Listeria monocytogenes is a Gram-positive facultative intracellular pathogen that can cause severe invasive infections upon ingestion with contaminated food. Clinically, listerial disease, or listeriosis, most often presents as bacteremia, meningitis or meningoencephalitis, and pregnancy-associated infections manifesting as miscarriage or neonatal sepsis. Invasive listeriosis is life-threatening and a main cause of foodborne illness leading to hospital admissions in Western countries. Sources of contamination can be identified through international surveillance systems for foodborne bacteria and strains' genetic data sharing. Large-scale whole genome studies have increased our knowledge on the diversity and evolution of L. monocytogenes, while recent pathophysiological investigations have improved our mechanistic understanding of listeriosis. In this article, we present an overview of human listeriosis with particular focus on relevant features of the causative bacterium, epidemiology, risk groups, pathogenesis, clinical manifestations, and treatment and prevention.

Characterization of a Listeria monocytogenes meningitis mouse model.

BACKGROUND: Listeria monocytogenes is a common cause of bacterial meningitis. We developed an animal model of listerial meningitis. METHODS: In survival studies, C57BL/6 mice received intracisternal injections with different L. monocytogenes sequence type 1 (ST1) colony forming units per milliliter (CFU; n = 48, 105, 106, 107, 108, and 109 CFU/ml). Second, mice were inoculated with 108 CFU/ml ST1 and sacrificed at 6 h and 24 h (n = 12/group). Outcome parameters were clinical score, CFUs, cyto- and chemokine levels, and brain histopathology. Third, 84 mice were inoculated (109 CFU/ml ST1) to determine optimal antibiotic treatment with different doses of amoxicillin and gentamicin. Fourth, mice were inoculated with 109 CFU/ml ST1, treated with amoxicillin, and sacrificed at 16 h and 24 h (n = 12/group) for outcome assessment. Finally, time point experiments were repeated with ST6 (n = 24/group). RESULTS: Median survival time for inoculation with 108 and 109 CFU/ml ST1 was 46 h and 40 h; lower doses of bacteria led to minimal clinical signs of disease. Brain levels of IL-6, IL-17A, and IFN-γ were elevated at 24 h, and IL-1ß, IL-6, IL-10, IFN-γ, and TNF-α were elevated in blood at 6 h and 24 h. Histopathology showed increased meningeal infiltration, vascular inflammation of meningeal vessels, hemorrhages, and ventriculitis. In the treatment model, brain levels of IL-6 and IL-17A and blood levels of IL-6 and IFN-γ were elevated. Compared to ST6, infection with ST1 led initially to higher levels of IL-1ß and TNF-α in blood and more profound neuropathological damage. At 16 h post inoculation, IL-1ß, IL-10, and TNF-α in blood and IL-6, IL17A, TNF-α, and IFN-γ levels in brain were higher in ST1 compared to ST6 without differences in CFUs between STs. At 24 h, neuropathology score was higher in ST1 compared to ST6 (p = 0.002) infected mice. CONCLUSIONS: We developed and validated a murine model of listerial meningitis. ST1-infected mice had a more severe inflammatory response and brain damage as compared to ST6-infected mice.

Histopathology of Listeria Meningitis.

Listeria monocytogenes meningitis is the third most common cause of bacterial meningitis in adults and has high mortality and morbidity rates. We describe the clinical course and score brain pathology of 5 patients who died of listeria meningitis. All patients were immunocompromised and ages ranged between 48 and 76 years. Three cases were confirmed by cerebrospinal fluid culture; one was confirmed by brain culture; and one diagnosis was based on a positive blood culture and neuropathological findings. Mild inflammation of meningeal arteries was found in 3 of 5 cases (60%). Moderate/severe ventriculitis was seen in 4 of 4 cases (100%), abscesses in 3 of 4 cases (75%), mild vascular inflammation in 4 of 5 cases (80%), mild/moderate hemorrhage in 2 of 4 cases (50%), mild/moderate thrombosis of meningeal artery in 3 of 5 cases (60%), and 1 case (25%) showed a moderate infarct. The inflammatory cells present in the meninges were characterized by a mix of monocytes, macrophages, and neutrophils and removal of apoptotic inflammatory cells by macrophages (efferocytosis). Gram stain showed intra- and extracellular presence of rod-shaped bacteria in 3 cases. Pathological examination was characterized by moderate to severe ventriculitis, abscesses and abundant efferocytosis which has been suggested to be exploited by L. monocytogenes for cell-to-cell spread.

Listeria monocytogenes meningitis in the Netherlands, 1985-2014: A nationwide surveillance study.

OBJECTIVES: Listeria monocytogenes can cause sepsis and meningitis. We report national surveillance data on L. monocytogenes meningitis in the Netherlands, describing incidence changes, genetic epidemiology and fatality rate. METHODS: We analyzed data from the Netherlands Reference Laboratory of Bacterial Meningitis for cases of L. monocytogenes meningitis. Strains were assessed by serotyping and bacterial population structure by multi-locus sequence typing. RESULTS: A total of 375 cases of Listeria meningitis were identified between 1985 and 2014. Peak incidence rates were observed in neonates (0.61 per 100,000 live births) and older adults (peak at 87 year; 0.53 cases per 100,000 population of the same age). Neonatal listerial meningitis decreased 17-fold from 1.95 per 100,000 live births between 1985 and 1989, to 0.11 per 100,000 live births between 2010 and 2014. Overall case fatality rate was 31%, in a multivariate analysis older age and concomitant bacteremia were associated with mortality (both p < 0.01). Clonal complexes (CC) CC1, CC2 and CC3 decreased over time from respectively 32% to 12%, 33% to 9% and 10% to 2% (all p < 0.001), while CC6 increased from 2% to 26% (p < 0.001). CONCLUSIONS: The incidence of neonatal listerial meningitis has declined over the past 25 years. The genotype CC6 has become the predominant genotype in listerial meningitis in the Netherlands. Mortality of listeria meningitis has remained high.

Cerebrospinal fluid inflammatory markers in patients with Listeria monocytogenes meningitis.

BACKGROUND: Listeria monocytogenes meningitis is the third most common cause of bacterial meningitis and is associated with high rates of mortality and unfavorable outcome. METHODS: We analyzed 101 cytokines, chemokines and complement factors in CSF of adult patients with Listeria meningitis included in a prospective cohort study and compared these biomarkers between Listeria meningitis patients and negative controls, and between Listeria meningitis patients with a favorable and an unfavorable outcome. RESULTS: CSF was available from 26 of 62 (42%) Listeria meningitis patients and 19 negative controls. Fifteen (58%) Listeria meningitis patients had an unfavorable outcome. In Listeria meningitis CSF levels of 51 biomarkers were significantly elevated compared to negative controls after Bonferroni correction. The 11 most significantly elevated (P < .01) biomarkers of unfavorable outcome in Listeria meningitis were markers of T-cell activation (sIL-2Rα, sCD40L and IL-1), interferon-related (IFN-α2, IL-18, CX3CL1, CCL20), markers of complement activation (C3a), and endothelial growth factor related (VEGF, CXCL7). CONCLUSIONS: Our data suggest that T-cell activation, complement activation, interferon- and endothelial growth factor production are important in the immune response to Listeria meningitis, and thereby influence outcome. GENERAL SIGNIFICANCE: Our study provides target pathways for further studies in the pathophysiology of Listeria meningitis.

Listeria monocytogenes sequence type 6 and increased rate of unfavorable outcome in meningitis: epidemiologic cohort study.

BACKGROUND: We analyzed clinical characteristics, treatment, genetic diversity, and outcome of 92 adults with Listeria monocytogenes meningitis included in 2 prospective nationwide cohort studies. METHODS: Episodes of community-acquired listerial meningitis confirmed by cerebrospinal fluid culture were included from 1998 to 2002 and 2006 to 2012. We compared patients and pathogen characteristics between cohorts and identified predictors for an unfavorable outcome according to the Glasgow Outcome Scale. RESULTS: Thirty episodes were included from 1998 to 2002 and 62 from 2006 to 2012; clinical and laboratory characteristics on admission were similar between cohorts. However, the rate of unfavorable outcome increased from 27% in the 1998-2002 cohort to 61% in the 2006-2012 cohort (P = .002). Differences between cohorts were increased use of adjunctive dexamethasone therapy (0% in 1998-2002 vs 53% in 2006-2012; P < .001) and emergence of infection by L. monocytogenes genotype sequence type 6 (ST6; 4% in 1998-2002 vs 29% in 2006-2012; P = .009). Multivariate regression analysis identified infection with L. monocytogenes ST6 as the sole predictor of unfavorable outcome (odds ratio, 3.77; 95% confidence interval, 1.07-13.33). Patients infected with genotypes other than ST6 also had an increased rate of unfavorable outcome over time (P = .03). CONCLUSIONS: The rate of unfavorable outcome among adults with listerial meningitis has increased over a 14-year period, from 27% to 61%. The emerging L. monocytogenes genotype ST6 was identified as the main factor leading to poorer prognosis. Adjunctive dexamethasone may be discontinued if L. monocytogenes is identified, as there is no proven benefit in Listeria meningitis.