Comparative analysis of European bat lyssavirus 1 pathogenicity in the mouse model

Eggerbauer, Elisa; Pfaff, Florian; Finke, Stefan; Höper, Dirk W.; Beer, Martin; Mettenleiter, Thomas C.; Nolden, Tobias; Teifke, Jens Peter; Müller, Thomas; Freuling, Conrad Martin

doi:10.1371/journal.pntd.0005668

Cited by 14 publications

(18 citation statements)

References 61 publications

(68 reference statements)

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“…However, this does not seem to be the case for the southern part of Europe. Finally, this study using 82 EBLV-1 nearly complete genome sequences does not support the existence of a third lineage named EBLV-1c as recently proposed by Eggerbauer et al (2017) . The sequences designed as EBLV-1c in this study correspond to lineage B5 in our study ( fig.…”

Section: Discussioncontrasting

confidence: 76%

Host Genetic Variation Does Not Determine Spatio-Temporal Patterns of European Bat 1 Lyssavirus

Troupin

Dellicour

Casadémont

et al. 2017

Genome Biology and Evolution

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The majority of bat rabies cases in Europe are attributed to European bat 1 lyssavirus (EBLV-1), circulating mainly in serotine bats (Eptesicus serotinus). Two subtypes have been defined (EBLV-1a and EBLV-1b), each associated with a different geographical distribution. In this study, we undertake a comprehensive sequence analysis based on 80 newly obtained EBLV-1 nearly complete genome sequences from nine European countries over a 45-year period to infer selection pressures, rates of nucleotide substitution, and evolutionary time scale of these two subtypes in Europe. Our results suggest that the current lineage of EBLV-1 arose in Europe ∼600 years ago and the virus has evolved at an estimated average substitution rate of ∼4.19×10−5 subs/site/year, which is among the lowest recorded for RNA viruses. In parallel, we investigate the genetic structure of French serotine bats at both the nuclear and mitochondrial level and find that they constitute a single genetic cluster. Furthermore, Mantel tests based on interindividual distances reveal the absence of correlation between genetic distances estimated between viruses and between host individuals. Taken together, this indicates that the genetic diversity observed in our E. serotinus samples does not account for EBLV-1a and -1b segregation and dispersal in Europe.

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Section: Discussioncontrasting

confidence: 76%

Host Genetic Variation Does Not Determine Spatio-Temporal Patterns of European Bat 1 Lyssavirus

Troupin

Dellicour

Casadémont

et al. 2017

Genome Biology and Evolution

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“…dose inoculation, and, as observed here (Supplementary Figure S3), was apathogenic at low dose i.m. infection [51].…”

Section: Discussionmentioning

confidence: 99%

“…Three-to four-week-old BALB/c mice (Charles-River, Germany) were infected with rRABV Rac, rCVS-11, ERA, and SAD L16 viruses using two different inoculation routes and two different viral doses, essentially as described before [51]. Two groups of six animals each were anesthetized and infected i.m.…”

Section: Brain Samples and Mouse Infectionsmentioning

confidence: 99%

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

Potratz

Zaeck

Christen

et al. 2020

Cells

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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.Cells 2020, 9, 412 2 of 20 M [4-10], and neuronal survival regulation by G [11][12][13][14]. Most pathogenicity studies, however, were performed on already attenuated virus backbones. Thus, differences in their ability to cause disease between highly virulent field virus isolates and lab-adapted, less pathogenic RABV strains are poorly understood. Moreover, it is unclear how molecular differences identified in virulent and attenuated viruses affect virus replication and spread in the infected animal and how the complex virus-host interplay eventually results in either disease or an abortive infection.In vivo, after infection of neurons, RABV spreads trans-synaptically from infected to connected neurons [15]. Retrograde axonal transport of RABV over long distances [16,17] along microtubules [18,19] is a key step in RABV neuroinvasion and is essential for infection of the central nervous system (CNS) through the peripheral nervous system. Co-internalization together with the neuronal p75NTR (tumor necrosis factor receptor superfamily member 16; TNFRSF16) receptor, subsequent retrograde axonal transport of RABV particles in endocytic vesicles, and post-replicative anterograde axonal transport of newly formed RABV have been visualized by live virus particle tracking in sensory neurons [20,21], emphasizing the capacity of hijacking neuron-specific machineries for long distance transport to synaptic membranes. However, internalization and axonal transport of lab-adapted viruses [20,21] together with the use of vaccine virus vectors for trans-syn...

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“…dose inoculation, and, as observed here (Supplementary Figure S3), was apathogenic at low dose i.m. infection [46].…”

Section: Discussionmentioning

confidence: 99%

“…Three-to four-week-old BALB/c mice (Charles-River, Germany) were infected with rRABV Rac, rCVS-11, ERA, and SAD L16 viruses using two different inoculation routes and two different viral doses, essentially as described before [46]. Two groups of six animals each were anesthetized and infected i.m.…”

Section: Brain Samples and Mouse Infectionsmentioning

confidence: 99%

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

Potratz¹,

Zaeck²,

Christen³

et al. 2020

Preprint

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Although conventional immunohistochemistry for neurotropic Rabies virus (RABV) usually shows a high preference for neurons, non-neuronal cells are also potential target cells and abortive infection of astrocytes 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 and quantitative comparison of astrocyte tropism in vivo is lacking. Here, a recently developed solvent-based tissue clearing technique was used to measure the RABV cell tropism in infected brains. Immunofluorescence analysis of 1 mm-thick tissue slices enabled 3D segmentation and quantification of infection frequencies of astrocytes and neurons. Comparison of highly virulent street virus clones from fox, dog, and raccoon with three lab strains of intermediate and low virulence revealed remarkable differences in the ability to infect astrocytes in vivo. While all viruses and infection routes led to comparable neuron infection frequencies, striking differences were detected for the infection of astrocytes. Consistent and inoculation route-independent astrocyte infection by field viruses, together with route-dependent or undetectable astrocyte infection by lab-adapted or vaccine viruses strongly suggests a model in which the ability to establish productive astrocyte infection in vivo functionally distinguishes field and attenuated lab RABV strains.

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Comparative analysis of European bat lyssavirus 1 pathogenicity in the mouse model

Cited by 14 publications

References 61 publications

Host Genetic Variation Does Not Determine Spatio-Temporal Patterns of European Bat 1 Lyssavirus

Host Genetic Variation Does Not Determine Spatio-Temporal Patterns of European Bat 1 Lyssavirus

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

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

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