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Open AccessArticle

Astrocyte Infection during Rabies Encephalitis Depends on the Virus Strain and Infection Route as Demonstrated by Novel Quantitative 3D Analysis of Cell Tropism

1
Friedrich-Loeffler-Institut (FLI), Federal Research Institute for Animal Health, Institute of Molecular Virology and Cell Biology, 17493 Greifswald-Insel Riems, Germany
2
Thescon GmbH, 48653 Coesfeld, Germany
3
ViraTherapeutics GmbH, 6020 Innsbruck, Austria
*
Author to whom correspondence should be addressed.
Cells 2020, 9(2), 412; https://doi.org/10.3390/cells9020412
Received: 14 January 2020 / Revised: 1 February 2020 / Accepted: 5 February 2020 / Published: 11 February 2020
(This article belongs to the Special Issue Cell Biology of Viral Infections)
Although conventional immunohistochemistry for neurotropic rabies virus (RABV) usually shows high preference for neurons, non-neuronal cells are also potential targets, and abortive astrocyte infection is considered a main trigger of innate immunity in the CNS. While in vitro studies indicated differences between field and less virulent lab-adapted RABVs, a systematic, quantitative comparison of astrocyte tropism in vivo is lacking. Here, solvent-based tissue clearing was used to measure RABV cell tropism in infected brains. Immunofluorescence analysis of 1 mm-thick tissue slices enabled 3D-segmentation and quantification of astrocyte and neuron infection frequencies. Comparison of three highly virulent field virus clones from fox, dog, and raccoon with three lab-adapted strains revealed remarkable differences in the ability to infect astrocytes in vivo. While all viruses and infection routes led to neuron infection frequencies between 7–19%, striking differences appeared for astrocytes. Whereas astrocyte infection by field viruses was detected independent of the inoculation route (8–27%), only one lab-adapted strain infected astrocytes route-dependently [0% after intramuscular (i.m.) and 13% after intracerebral (i.c.) inoculation]. Two lab-adapted vaccine viruses lacked astrocyte infection altogether (0%, i.c. and i.m.). This suggests a model in which the ability to establish productive astrocyte infection in vivo functionally distinguishes field and attenuated lab RABV strains.
Keywords: rabies; uDISCO; 3D imaging; rabies pathogenicity; astrocyte infection rabies; uDISCO; 3D imaging; rabies pathogenicity; astrocyte infection
MDPI and ACS Style

Potratz, M.; Zaeck, L.; Christen, M.; te Kamp, V.; Klein, A.; Nolden, T.; Freuling, C.M.; Müller, T.; Finke, S. Astrocyte Infection during Rabies Encephalitis Depends on the Virus Strain and Infection Route as Demonstrated by Novel Quantitative 3D Analysis of Cell Tropism. Cells 2020, 9, 412.

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