Role of Bacterial and Host DNases on Host-Pathogen Interaction during Streptococcus suis Meningitis
Abstract
:1. Introduction
2. Results
2.1. SsnA Only Slightly Increases S. suis Virulence in Pigs
2.2. NETs Are Formed in CSF and Consist of PR-39 at the Onset of Meningitis
2.3. NET-Markers Are Present in Meninges, but No NET-Fibers Are Detectable in Brain Tissue
2.4. Host DNases Are Active during S. suis Meningitis in Brain Tissue, CSF and Serum
2.5. DNase 1 Has No Impact on Transmigration of Neutrophils through a Choroid Plexus Epithelial Cell Layer
2.6. DNase 1 Partially Improves Killing of S. suis by Neutrophils of Individual Animals in CSF
3. Discussion
4. Materials and Methods
4.1. Bacterial Strains and Growth Conditions
4.2. Experimental Infection of Piglets
4.3. Survival Experiment
4.4. Early Phase Experiment
4.5. Sample Collection
4.6. Re-Isolation of Infection Strains
4.7. Blood Survival Assay
4.8. Pico Green Quantification Assay
4.9. Histology of the Brain
4.10. Cytospin of CSF
4.11. Staining and Microscopy
4.11.1. Staining of CSF in CellView® Slides
- Staining of NETs and S. suis: CSF was fixed with 4% paraformaldehyde (Science Services, E15710-25, Munich, Germany). Staining was performed as previously described [2] using as first antibodies mouse IgG2a anti-DNA/histone (Millipore MAB3864; 0.55 mg; 1:1000, Billerica, MA, USA) and rabbit IgG anti-PR39 (1:75) or rabbit IgG anti-S. suis [19] (1:500). After washing, the DNA was stained with aqueous Hoechst 33,342 (Stock 50mg/mL, Sigma B-2261, St. Louis, MO, USA) and covered with ProLong™ Gold Antifade Mountant (Invitrogen, P36930, Carlsbad, CA, USA). The samples were examined microscopically on a Leica TCS SP5 AOBS confocal inverted-base fluorescence microscope with a HCX PL APO 40 × 0.75–1.25 oil immersion objective with an Argon, 405 nm and 633 nm laser. The settings were adjusted using isotype control antibodies in separate preparations.
- Staining of NETs and intra- and extracellular S. suis: staining was performed as previously described [2] using first antibodies mouse IgG2a anti-DNA/histone (Millipore MAB3864, Billerica, MA, USA; 0.55 mg; 1:1000) and rabbit IgG anti-S. suis [19] (1:500). After washing the DNA was stained with aqueous Hoechst 33,342 [(Stock 50 mg/mL, Sigma B-2261, St. Louis, MO, USA) and covered with ProLong™ Gold Antifade Mountant (Invitrogen, P36930, Carlsbad, CA, USA). The samples were examined microscopically on a Leica TCS SP5 AOBS confocal inverted-base fluorescence microscope with a HCX PL APO 40 × 0.75–1.25 oil immersion objective with an Argon, 405 nm, 561 nm and 633 nm laser. The settings were adjusted using isotype control antibodies in separate preparations.
4.11.2. Staining of Slides
4.11.3. Staining of 2–4 µm Paraffin Embedded Brain Sections
- Hematoxylin-Eosin (HE) Staining: Automated dying in LEICA ST 4040 with 0.1 % hematoxylin (Roth, Karlsruhe, Germany) and 1 % eosin (Roth, Karlsruhe, Germany).
- Immunofluorescence Staining: The staining was performed as previously described [12] with the following changes. First antibodies mouse IgG2a anti-DNA/histone (Millipore MAB3864, Billerica, MA, USA; 0.55 mg; 1:100) or mouse anti-PR-39 (Lionex, Braunschweig, Germany; 1:100) and rabbit anti-elastase (Abcam, ab1876, Cambridge, UK; 1:50) or rabbit IgG anti-S. suis [19] (1:500) or rabbit anti-DNase 1 (Invitrogen; PA5-22017, Carlsbad, CA, USA; 1:100) dissolved in blocking buffer were incubated overnight 4 °C, while gently shaking. The samples were examined microscopically on a Leica TCS SP5 AOBS confocal inverted-base fluorescence microscope with HCX PL APO 40 × 0.75–1.25 and HCX PL APO lambda blue 63 × 1.40 oil immersion objectives with an Argon, 405 nm and 633 nm laser. The settings were adjusted using isotype control antibodies in separate preparations.
4.12. DNase Activity Test
4.13. DNase 1, PR-39, PMAP-23, PMAP-37 ELISA
4.14. Cell Culture
- Cell Culture Model of the Porcine Blood–CSF Barrier (Figure 5A): After three days’ incubation, transepithelial electrical resistance (TEER) was measured with a Millicell® ERS-2 (Millipore, Billerica, MA, USA) voltmeter to control the barrier density. Some filters were infected with S. suis 10 for one hour in the blood compartment. Before adding the freshly isolated porcine neutrophils, medium in the blood compartment was changed in all filters. Transmigration of neutrophils was performed for 4 h at 37 °C and 5% CO2. Serial dilutions of transmigrated bacteria were plated on blood agar (Columbia Agar with 7% Sheep Blood; Thermo Scientific™ PB5008A, Waltham, MA, USA) to determine the CFU/mL and 250 µL medium of the CSF compartment was fixed with a final concentration of 4% PFA (Paraformaldehyde 16% Science Services E15710, Munich, Germany) for flow cytometric analysis. TEER was measured again. The experiment was repeated three times on independent days.
- Cell Culture Model of the Porcine Blood–CSF Barrier Mimicking Physiological Conditions (Figure 6): Filters were transferred in new wells with 990 µL pooled CSF of healthy piglets (euthanasia of these pigs was approved and registered by the local Animal Welfare Officer in accordance with the German Animal Welfare Law under number TiHo-T-2019-14, last update 07/2019). To attract neutrophils, 50 ng interleukin 8 (IL8) (Recombinant Porcine IL-8/CXCL8, R&D Systems 535-IN-025, Minneapolis, MN, USA) was added to all wells. To half of the wells, 20 U DNase 1 (Serva 18535.02) was added. CSF of half of the wells was infected with 1–2 × 102 CFU S. suis 10. Thus ultimately yielded: non-infected wells, non-infected wells with DNase 1, infected wells and infected wells with DNase 1. In the upper compartment, 400 µL heparinized whole pig blood (animal permit registered at the Lower Saxonian State Office for Consumer Protection and Food Safety (Niedersächsisches Landesamt für Verbraucherschutz und Lebensmittelsicherheit) under no. 33.9-42502-05-18A302, last update 07/2018) was added and incubated at 37 °C and 5% CO2 for 4 h. After incubation, serial dilutions of CSF were plated on blood agar plates (Columbia Agar with 7% Sheep Blood; Thermo Scientific™ PB5008A, Waltham, MA, USA) to determine the CFU/mL, and 250 µL CSF was fixed with a final concentration of 4% PFA (Paraformaldehyde 16% Science Services E15710, Munich, Germany) for flow cytometric analysis. TEER was measured again. The experiment was repeated five times on independent days. CSF was collected from healthy euthanized pigs. The euthanasia of these pigs was approved and registered by the local Animal Welfare Officer in accordance with the German Animal Welfare Law under number TiHo-T-2019-14.
4.15. Flow Cytometry
4.16. Neutrophil Isolation
4.17. Neutrophil Killing Assay
4.18. Statistical Analysis
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Meurer, M.; Öhlmann, S.; Bonilla, M.C.; Valentin-Weigand, P.; Beineke, A.; Hennig-Pauka, I.; Schwerk, C.; Schroten, H.; Baums, C.G.; Köckritz-Blickwede, M.v.; et al. Role of Bacterial and Host DNases on Host-Pathogen Interaction during Streptococcus suis Meningitis. Int. J. Mol. Sci. 2020, 21, 5289. https://doi.org/10.3390/ijms21155289
Meurer M, Öhlmann S, Bonilla MC, Valentin-Weigand P, Beineke A, Hennig-Pauka I, Schwerk C, Schroten H, Baums CG, Köckritz-Blickwede Mv, et al. Role of Bacterial and Host DNases on Host-Pathogen Interaction during Streptococcus suis Meningitis. International Journal of Molecular Sciences. 2020; 21(15):5289. https://doi.org/10.3390/ijms21155289
Chicago/Turabian StyleMeurer, Marita, Sophie Öhlmann, Marta C. Bonilla, Peter Valentin-Weigand, Andreas Beineke, Isabel Hennig-Pauka, Christian Schwerk, Horst Schroten, Christoph G. Baums, Maren von Köckritz-Blickwede, and et al. 2020. "Role of Bacterial and Host DNases on Host-Pathogen Interaction during Streptococcus suis Meningitis" International Journal of Molecular Sciences 21, no. 15: 5289. https://doi.org/10.3390/ijms21155289