BornavirusBornavirus

David L. DowellDavid L. Dowell

MCB5505MCB5505

04/14/0404/14/04

BornavirusBornavirus

Order: MononegaviralesOrder: Mononegavirales Family: BornaviridaeFamily: Bornaviridae

Single Genus: BornavirusSingle Genus: Bornavirus Borna Disease Virus (BDV) TSBorna Disease Virus (BDV) TS

Identified in 1926Identified in 1926

StructureStructure

Spherical envelopeSpherical envelope 90-130 nm diameter90-130 nm diameter Two types of glycoprotein spikes, GP43 Two types of glycoprotein spikes, GP43

and GP84 and GP84 Crescent-like inner coreCrescent-like inner core Nucleocapsid Nucleocapsid

60 nm diameter60 nm diameter 4 nm width4 nm width Contains a helical Ribonucleo protein Contains a helical Ribonucleo protein

complexcomplex

GenomeGenome

Negative sense, single strand RNANegative sense, single strand RNA Linear, single segmentLinear, single segment 8.9 kb long8.9 kb long Contains at least 6 open reading Contains at least 6 open reading

framesframes

•N: nucleoprotein (p40) •P: phosphoprotein (p24) •M: matrix protein (gp18) •G: envelope protein (gp94) •L: RNA-dependent RNA polymerase (p190) •X: unknown function (p10) - nuclear import function for other virus-encoded proteins?

Negative sense, single strand RNANegative sense, single strand RNA Linear, single segmentLinear, single segment 8.9 kb long8.9 kb long Contains at least 6 open reading Contains at least 6 open reading

framesframes Similarities in nucleotide sequence Similarities in nucleotide sequence

and ORF structure suggest close and ORF structure suggest close relation to Rhabdoviridae relation to Rhabdoviridae

GenomeGenome

VectorsVectors

Origin: 1894; Borna, a village in LeipzigOrigin: 1894; Borna, a village in Leipzig An illness of horsesAn illness of horses

Mostly mammals, but also ostrichesMostly mammals, but also ostriches Humans can self-infectHumans can self-infect

ReplicationReplication

EndocytosisEndocytosis Viral GP84 (also GP18) protein probably Viral GP84 (also GP18) protein probably

used for adsorption with unknown cellular used for adsorption with unknown cellular receptorreceptor

GP43 involved in pH-dependent fusion GP43 involved in pH-dependent fusion after internalizationafter internalization

Taken up by endosomesTaken up by endosomes

Replication (continued)Replication (continued)

Only known member of order Only known member of order Mononegavirales to replicate in nucleusMononegavirales to replicate in nucleus

Both (+) and (-) sense RNA in nucleusBoth (+) and (-) sense RNA in nucleus (+) sense localized in nucleolus(+) sense localized in nucleolus (-) sense (genomic) in both nucleolar and non-(-) sense (genomic) in both nucleolar and non-

nucleolar regionsnucleolar regions Subgenomic RNAs modified post-Subgenomic RNAs modified post-

transcriptionally by RNA splicingtranscriptionally by RNA splicing Specific details on replication and splicing Specific details on replication and splicing

mechanisms are still unknownmechanisms are still unknown

General SummaryGeneral Summary

Order: MononegaviralesOrder: Mononegavirales Enveloped, (-) sense, single strand, Enveloped, (-) sense, single strand,

linear, single segmented RNAlinear, single segmented RNA Similar to Rhabdoviridae in nucleotide Similar to Rhabdoviridae in nucleotide

sequence and ORF structuresequence and ORF structure Mammals, birds, humans can self-Mammals, birds, humans can self-

infectinfect Replicates in nucleusReplicates in nucleus

Host RangeHost Range Wide host range: mammals to birdsWide host range: mammals to birds Likely includes all warm-blooded Likely includes all warm-blooded

animalsanimals

Natural reservoir unknownNatural reservoir unknown Rodents proposed, but no evidence of Rodents proposed, but no evidence of

natural infection so theory remains natural infection so theory remains speculativespeculative

TransmissionTransmission

Intranasal infection shown by early Intranasal infection shown by early inflammation of olfactory bulbs of inflammation of olfactory bulbs of infected horsesinfected horses

Infection also by contact with bodily Infection also by contact with bodily secretions and excretions containing secretions and excretions containing BDV RNABDV RNA

Blood-borne transmission with BDV Blood-borne transmission with BDV RNA and protein in peripheral bloodRNA and protein in peripheral blood

All proposed theories; routes have yet All proposed theories; routes have yet to be fully provedto be fully proved

PathogenesisPathogenesis Noncytolytic, neurotropic Noncytolytic, neurotropic

virusvirus Causes Borna disease in horses Causes Borna disease in horses

and sheepand sheep Severe, frequently fatal neuro-Severe, frequently fatal neuro-

logical diseaselogical disease Progressive, nonpurulent encephalomyelitisProgressive, nonpurulent encephalomyelitis ““sad horse disease”sad horse disease”

Usually asymptomatic, BDV antibodies Usually asymptomatic, BDV antibodies found in clinically healthy horsesfound in clinically healthy horses

When present, symptoms include behavioral When present, symptoms include behavioral changes, hyperactivity and disturbances in changes, hyperactivity and disturbances in gait early in infection, and ataxia and gait early in infection, and ataxia and partial paralysis during terminal stages partial paralysis during terminal stages

NeuropathogenesisNeuropathogenesis

BDV migrates intraaxonally BDV migrates intraaxonally

towards CNS after early intra-towards CNS after early intra-

neuronal replicationneuronal replication Preferential tropism for limbic system, Preferential tropism for limbic system,

including hippocampusincluding hippocampus Regulation of memory, behavior and emotionsRegulation of memory, behavior and emotions Significant in human psychiatric disordersSignificant in human psychiatric disorders

Later infection can spread through Later infection can spread through peripheral nervous system and non-neural peripheral nervous system and non-neural organs and tissues if sustainedorgans and tissues if sustained

Neuropathogenesis Neuropathogenesis (continued)(continued)

Experimental infection results in inflammatory Experimental infection results in inflammatory reaction in the brainreaction in the brain Can cause neuronal degenerationCan cause neuronal degeneration Caudate nucleus, dentate gyrus, and hippocampusCaudate nucleus, dentate gyrus, and hippocampus

Speculation BDV is a zoonotic illness infecting Speculation BDV is a zoonotic illness infecting individuals occupationally exposed to animalsindividuals occupationally exposed to animals Received attention in the press who suggested BDV Received attention in the press who suggested BDV

infection possibly linked to rural suicide and infection possibly linked to rural suicide and depressiondepression

BDV-linked psychopathology is controversial BDV-linked psychopathology is controversial and significant substantiated proof is yet to be and significant substantiated proof is yet to be discovereddiscovered

Neuropathogenesis Neuropathogenesis (Therapy)(Therapy)

Amantadine and ribavirin both Amantadine and ribavirin both successfully used against bornavirussuccessfully used against bornavirus

Amantadine is a glutamate receptor Amantadine is a glutamate receptor antagonist may have antidepressant antagonist may have antidepressant effectseffects Still unclear as to whether this is Still unclear as to whether this is

due to its antiviral activity or due to its antiviral activity or

neurotransmitter system neurotransmitter system

modulationmodulation

Cool SummaryCool Summary Host Range: ostriches to horses to Indiana Host Range: ostriches to horses to Indiana

JonesJones Transmission routes: nasal cavity, Transmission routes: nasal cavity,

secretion/excretion contact, blood; theoreticalsecretion/excretion contact, blood; theoretical Borna disease in animalsBorna disease in animals

Neurological disease can cause encephalomyelitis, Neurological disease can cause encephalomyelitis, usually asymptomatic, but can cause behavioral usually asymptomatic, but can cause behavioral changes/psychological effectschanges/psychological effects

Virus progresses CNS, PNS, extra-nervousVirus progresses CNS, PNS, extra-nervous Speculation of BDV as zoonotic illness, but Speculation of BDV as zoonotic illness, but

unsubstantiatedunsubstantiated Amantadine/ribavirin possible treatmentAmantadine/ribavirin possible treatment

Antidepressant effects (amantadine) controversial Antidepressant effects (amantadine) controversial stemstem

ReferencesReferences Bornavirus: Microbiology & Immunology; Bornavirus: Microbiology & Immunology;

http://www-micro.msb.le.ac.uk/3035/Bornavirus.hthttp://www-micro.msb.le.ac.uk/3035/Bornavirus.htmlml

Bornavirus; Bornavirus; www.vu-wien.ac.at/i123/spezvir/www.vu-wien.ac.at/i123/spezvir/bornavirusbornavirus1.html1.html

Bornavirus; Bornavirus; http://www.stanford.edu/group/virus/1999/monical/http://www.stanford.edu/group/virus/1999/monical/bornavirus.htmlbornavirus.html

The nervous system; The nervous system; http://www.emc.maricopa.edu/faculty/farabee/BIOhttp://www.emc.maricopa.edu/faculty/farabee/BIOBK/BioBookNERV.htmlBK/BioBookNERV.html

Bornavirus; Bornavirus; www.rki.de/PRESSE/PD_THEMA/BORNA.HTMwww.rki.de/PRESSE/PD_THEMA/BORNA.HTM

Limbic System: The Center of Emotions Limbic System: The Center of Emotions http://www.epub.org.br/cm/n05/mente/limbic_i.htmhttp://www.epub.org.br/cm/n05/mente/limbic_i.htm

ANY QUESTIONS???ANY QUESTIONS???