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01.12.2018 | Research | Ausgabe 1/2018 Open Access

Journal of Neuroinflammation 1/2018

Characterization of a Listeria monocytogenes meningitis mouse model

Zeitschrift:
Journal of Neuroinflammation > Ausgabe 1/2018
Autoren:
Merel M. Koopmans, JooYeon Engelen-Lee, Matthijs C. Brouwer, Valery Jaspers, Wing Kit Man, Mercedes Vall Seron, Diederik van de Beek
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1186/​s12974-018-1293-3) contains supplementary material, which is available to authorized users.

Abstract

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-1β, 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-1β and TNF-α in blood and more profound neuropathological damage. At 16 h post inoculation, IL-1β, 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.
Zusatzmaterial
Additional file 1: This table shows a histopathological scoring method of brain tissue in bacterial meningitis mouse model which has been used in this study and previously has been used in a pneumococcal meningitis model. (DOC 48 kb)
12974_2018_1293_MOESM1_ESM.doc
Additional file 2: Kaplan-Meier survival curve (A) in male and female mice (24 mice/group). Clinical score of the treatment survival experiments (12 mice/ group) inoculated with 109 CFU bacteria and treated with antibiotics. Abbreviation; h = hours (PDF 30 kb)
12974_2018_1293_MOESM2_ESM.pdf
Additional file 3: This table shows histopathological scoring of brain tissue in listerial meningitis time point studies with L. monocytogenes ST1 and ST6 strains. Results are presented based on number of mice and on median pathology score. (DOC 82 kb)
12974_2018_1293_MOESM3_ESM.doc
Additional file 4: Kaplan-Meier survival curves in treatment survival experiments inoculated with 109 CFU/ml (A and B) and with 108 CFU/ml (C) and bacterial outgrowth after inoculation with 109 CFU/ml L. monocytogenes ST1 and amoxicillin treatment (D). --- lower limit of detection, Abbreviation; h = hours. (PDF 44 kb)
12974_2018_1293_MOESM4_ESM.pdf
Additional file 5: This table shows bacterial outgrowth in brain homogenate in mice infected with L. monocytogenes ST1 and treated with antibiotics during survival experiments (70 h post inoculation). Every bacterial count represents one mouse. (DOC 51 kb)
12974_2018_1293_MOESM5_ESM.doc
Additional file 6: (A) Median clinical score in ST1 and ST6 inoculated mice in the non-treatment model with interquartile ranges, (B) Bacterial outgrowth in the non-treatment model ST1 vs. ST6 6 h after inoculation. Titres are expressed per mice and with median CFU/ml or CFU/mg. (PDF 38 kb)
12974_2018_1293_MOESM6_ESM.pdf
Additional file 7: This table shows the brain and plasma levels of cytokines in mice infected with 109 CFU/ml L. monocytogenes ST1 or ST6 at time points 16 and 24 h and treated with 100 mg/kg/24 h amoxicillin after 16 h. (DOC 64 kb)
12974_2018_1293_MOESM7_ESM.doc
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