title: Borna disease virus-induced neuronal degeneration dependent on host genetic background and prevented by soluble factors.
abstract: Infection of newborn rats with Borne disease virus (BDV) results in selective degeneration of granule cell neurons of the dentate gyrus (DG). To study cellular countermechanisms that might prevent this pathology, we screened for rat strains resistant to this BDV-induced neuronal degeneration. To this end, we infected hippocampal slice cultures of different rat strains with BDV and analyzed for the preservation of the DG. Whereas infected cultures of five rat strains, including Lewis (LEW) rats, exhibited a disrupted DG cytoarchitecture, slices of three other rat strains, including Sprague-Dawley (SD), were unaffected. However, efficiency of viral replication was comparable in susceptible and resistant cultures. Moreover, these rat strain-dependent differences in vulnerability were replicated in vivo in neonatally infected LEW and SD rats. Intriguingly, conditioned media from uninfected cultures of both LEW and SD rats could prevent BDV-induced DG damage in infected LEW hippocampal cultures, whereas infection with BDV suppressed the availability of these factors from LEW but not in SD hippocampal cultures. To gain further insights into the genetic basis for this rat strain-dependent susceptibility, we analyzed DG granule cell survival in BDV-infected cultures of hippocampal neurons derived from the F1 and F2 offspring of the crossing of SD and LEW rats. Genome-wide association analysis revealed one resistance locus on chromosome (chr) 6q16 in SD rats and, surprisingly, a locus on chr3q21-23 that was associated with susceptibility. Thus, BDV-induced neuronal degeneration is dependent on the host genetic background and is prevented by soluble protective factors in the disease-resistant SD rat strain.
authors: Department of Virology, Spemann Graduate School of Biology and Medicine, Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany.
authors: Yuan-Ju
authors: YJ
authors: Wu
authors: Herbert
authors: H
authors: Schulz
authors: Chia-Ching
authors: CC
authors: Lin
authors: Kathrin
authors: K
authors: Saar
authors: Giannino
authors: G
authors: Patone
authors: Heike
authors: H
authors: Fischer
authors: Norbert
authors: N
authors: Hübner
authors: Bernd
authors: B
authors: Heimrich
authors: Martin
authors: M
authors: Schwemmle
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001685:Biological Factors / Q000737:chemistry / Q000494:pharmacology; D001891:Borna disease virus / Q000502:physiology*; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002874:Chromosome Mapping; D033481:Chromosomes, Mammalian / Q000235:genetics; D017077:Culture Media, Conditioned / Q000737:chemistry / Q000494:pharmacology; D018891:Dentate Gyrus / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D060467:Disease Resistance / Q000235:genetics; D005260:Female; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology / Q000821:virology; D054884:Host-Pathogen Interactions; D008297:Male; D009410:Nerve Degeneration / Q000235:genetics / Q000517:prevention & control / Q000821:virology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D020641:Polymorphism, Single Nucleotide; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013045:Species Specificity; D046509:Tissue Culture Techniques
chemical_list: D001685:Biological Factors; D019208:Brain-Derived Neurotrophic Factor; D017077:Culture Media, Conditioned