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Strain-dependent effects of clinical echovirus 30 outbreak isolates at the blood-CSF barrier
Tobias Dahm1, Ortwin Adams2, Sindy Boettcher3
1Pediatric Infectious Diseases, University Children's Hospital Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Background:
Echovirus (E) 30 (E-30) meningitis is characterized by neuroinflammation involving immune cell pleocytosis at the protective barriers of the central nervous system (CNS). In this context, infection of the blood-cerebrospinal fluid barrier (BCSFB), which has been demonstrated to be involved in enteroviral CNS pathogenesis, may affect the tight junction (TJ) and adherens junction (AJ) function and morphology.
Methods:
We used an in vitro human choroid plexus epithelial (HIBCPP) cell model to investigate the effect of three clinical outbreak strains (13-311, 13-759, and 14-397) isolated in Germany in 2013, and compared them to E-30 Bastianni. Conducting transepithelial electrical resistance (TEER), paracellular dextran flux measurement, quantitative real-time polymerase chain reaction (qPCR), western blot, and immunofluorescence analysis, we investigated TJ and AJ function and morphology as well as strain-specific E-30 infection patterns. Additionally, transmission electron and focused ion beam microscopy electron microscopy (FIB-SEM) was used to evaluate the mode of leukocyte transmigration. Genome sequencing and phylogenetic analyses were performed to discriminate potential genetic differences among the outbreak strains.
Results:
We observed a significant strain-dependent decrease in TEER with strains E-30 Bastianni and 13-311, whereas paracellular dextran flux was only affected by E-30 Bastianni. Despite strong similarities among the outbreak strains in replication characteristics and particle distribution, strain 13-311 was the only outbreak isolate revealing comparable disruptive effects on TJ (Zonula Occludens (ZO) 1 and occludin) and AJ (E-cadherin) morphology to E-30 Bastianni. Notwithstanding significant junctional alterations upon E-30 infection, we observed both para- and transcellular leukocyte migration across HIBCPP cells. Complete genome sequencing revealed differences between the strains analyzed, but no explicit correlation with the observed strain-dependent effects on HIBCPP cells was possible.
Conclusion:
The findings revealed distinct E-30 strain-specific effects on barrier integrity and junctional morphology. Despite E-30-induced barrier alterations leukocyte trafficking did not exclusively occur via the paracellular route.
Insights
Echovirus 30 (E-30) meningitis impacts central nervous system barriers. Different E-30 strains cause varied effects on barrier integrity and immune cell migration, influencing neuroinflammation.
Area of Science:
- Virology
- Neuroscience
- Immunology
Background:
- Echovirus 30 (E-30) meningitis causes neuroinflammation at central nervous system (CNS) barriers.
- Infection of the blood-cerebrospinal fluid barrier (BCSFB) by enteroviruses can disrupt tight junction (TJ) and adherens junction (AJ) integrity.
Purpose of the Study:
- To investigate the impact of different Echovirus 30 (E-30) strains on the human choroid plexus epithelial (HIBCPP) cell model.
- To analyze strain-specific effects on TJ and AJ function, morphology, and leukocyte transmigration.
Main Methods:
- Utilized an in vitro HIBCPP cell model with clinical E-30 outbreak strains.
- Assessed barrier integrity using transepithelial electrical resistance (TEER) and dextran flux.
- Analyzed TJ/AJ morphology via immunofluorescence and microscopy; performed qPCR, western blot, and genome sequencing.
Main Results:
- E-30 strains demonstrated strain-dependent effects on barrier integrity, with significant TEER decrease observed for E-30 Bastianni and strain 13-311.
- Strain 13-311 showed comparable disruptive effects on TJ (ZO-1, occludin) and AJ (E-cadherin) morphology to E-30 Bastianni.
- Leukocyte migration occurred through both paracellular and transcellular routes despite junctional alterations.
Conclusions:
- Distinct E-30 strains exert specific effects on BCSFB integrity and junctional morphology.
- Leukocyte trafficking across the BCSFB is not solely dependent on the paracellular route, even with E-30-induced barrier damage.
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