Members of the flaviviridae family

Pestiviruses - very important group of animal pathogens

Flaviviruses - arthropod borne, important human pathogens 

Hepatoviruses - hepatitis C virus 

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Flaviviridae molecular biology

morphology - 

  • 60-80nm icosahedral particles composed of a single capsid protein (C) surrounded by a tightly adherent envelope
  • particles are not very stable in the environment 
  • particles contain an 11-12Kb single stranded +ve sense RNA genome
  • Envelope consists of 3 viral glycoproteins - E1, E2 and E3 (Erns in BVDV)
  • genome encodes single large polyprotein - proteolyticllay processed by combination of viral and host proteases 
  • protein Npro - potent interferon response antagonist 
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Pestivirus diseases of animals

Bovine viral diarrhoea virus genotype 1 (BVDV 1) - infects cattle sheep and deer

Bovine viral diarrhoea virus genotype 2 (BVDV 2) - infects cattle and sheep and can cause more severe acute disease than BVDV1 

Border Disease virus - distinct variant of BVDV that infects sheep

Classial Swine Fever virus - (Hog cholera virus) - infects swine

All four are serologically related and are all immunosuppresive 

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Bovine Viral Diarrhoea virus 1

Causes 2 distinct diseases: 

  • acute bovine viral diarrhoea (BVD)
  • mucosal disease (MD)
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Bovine Viral Diarrhoea

  • majority of infections are sub-clinical even in non-immune cattle
  • usually causes trivial illness lasting a few days 
  • high morbidity, low mortality 
  • coughing and diarrhoea
  • immunosuppressive action of virus during times of stress predisposes to mixed infection with Pasteurella hemolytica, exacerbates the respiratory disease - stress induced pneumonia or shipping fever - very severe brochopneumonia 
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Bovine Viral Diarrhoea Pathogenesis

  • Incubation 4-7 days. Duration ~10 days post infection. 
  • primary replication in oral mucosa, transmission to the palatine tonsil 
  • widespread dissemination via blood as free virus or infected lymphocytes and monocytes to many tissues - especially lymphoid organs
  • causes mild fever, leukopenia and diarrhoea 
  • virulent strains (BVDV 2 strains) cause severe thrombocytopenia and associated haemorrhagic consequences 
  • BVDV antigen can be detected in many tissues of infected animal and is primarily associated with monocytes and follicular dendritic cells 
  • most deleterious consequences of BVDV infections are associated with one, or more aspects of the reproductive physiology 
  • conception rates can be reduced by 50% following BVDV infection - abortion, reabsorption, infection of ovaries and oviduct cells, reduced eostradiol secretion and LH burst - loss of milk production - congential defects - persistently infected calves
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Cytopathic and Non-cytopathic biotypes

  • Most BVDV viruses grow in cell culture without causing CPE and are designated noncytopathic strains 
  • some strains are cytopathic and are particularly associated with mucosal disease 
  • only ncp strains can cause persistent infections as they are able to inhibit induction of IFN by dsRNA during infection - enables them to establish persistent infection in the foetus
  • cp strains cant do this and will usually cause abortion or foetal damage depending on stage of gestation 
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Consequences of in utero infection

  • <18dpc (pre-implanted) infection does not occur
  • <25dpc (early pregnancy) leads to embryonic death and reabsorption (cp/ncp strains)
  • 25-90 days - retarded growth/look normal but are persistently infected (PI) and tolerant - excrete large quantities of virus 
    • only ncp strains can do this
    • occurs in window of opportunity where foetus's acquired immunity is developing - viral antigen is recognised as host antigen 
  • 80-125 days  - congential defects of the eye and CNS effects (retinal dysplasia and cerebral hypoplasia)
  • 125 - 180 days - calves may survive, develop neutralising antibody and clear virus, high incidence of congential abnormalities - late gestation infections result in clinically normal calves with high levels of pre-colostral antibodies - immune for life but prone to other disease
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Significance of PI animals

  • small and unthrifty but not always 
  • never seroconvert  (create Ab) to virus they are carrying - may partially respond to antigenically distinct strains 
  • likely to succumb to mucosal disease eventually - many die between 6-24 months as maternal antibody wanes
  • extremely efficient transmitters of infection to non-immune animals
  • provide long-term reservoir for maintaining the virus in the population, hence ncp strains predominate 
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Transmission of BVDV

  • rate of spread depends on stocking density and prevalence of PI animals 
  • transmission from PI animals is much more efficient than from acutely infected animals 
  • occurs by direct contact - 1hr nose to nose contact sufficient - contact with feed contaminated with urine, nasal secretions, faeces, aborted foetuses and placentas 
  • can be transmitted iatrogenically - contaminated gloves 
  • semen from PI bulls is highly infectious - rarely but can lead to PI offspring, embryos from PI or acutely infected animals can be infected 
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Mucosal Disease (1)

  • only occurs in PI animals 
  • extensive ulceration of GI tract, necrotic lesions in the mouth, profuse diarrhoea containing fresh or clotted blood 
  • death 2 weeks after onset of clinical signs - 100%
  • animals are infected with cp and ncp strains simultaneously - "virus pair" - results from spontaneous mutation of ncp strain to cp form in PI animals - antigenically very similar/identical 
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Mucosal Disease (2)

  • cp mutation increases the expression of viral protein NS3 - serine protease, helicase and NTPase 
  • unrestrained replication, high levels of dsRNA and apoptosis -  resulting cell death manifests as mucosal disease 
  • transmission of cp virus to other PI animals leads to mucosal disease storm 
  • transmission to PI animals with antigenically distinct strain produces slower progressing form of the disease - chronic MD - partial immune response but death is still inevitable (when cp and ncp strains recombine usually)
  • MD may also be triggered by live-attenuated vaccines which are usually based on cp variants
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Summary of Events leading to MD

  • non-immune pregnant cow becomes infected with ncp strain of BVDV
  • virus readily crosses placenta to infect the foetus
  • cow mounts a successful immune response and recovers (life long immunity)
  • ncp virus evades foetal innate immunity by blocking IFN expression. Immature immune system of foetus becomes tolerant to virus 
  • persistently infected calf is born - never seroconverts and sheds virus all its life 
  • ncp virus mutates to cp phenotype or calf is infected with virus from another source 
  • inability of PI animal to respond to cp virus infection leads to extensive tissue damage and death from mucosal disease 
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Severe acute BVD

  • second genotype of BVDV recognised in recent years - BVDV2 
  • associated with more severe primary acute infection - esp. Canada/USA
  • acute disease caused by virulent strains of BVDV2 is characterised by fever, diarrhoea, thrombocytopaenia, haemorrhages, respiratory disorders, high abortion and mortality rates 
  • UK strain of BVDV2 is less virulent 
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  • introduction of infected animals into naive herd results in rapid spread and dramatic losses (50% of calves lost in first year due to MD) - following year stable equilibrium is reached - 85% animals are immune and 1-2% PI - outbreaks of BVD occur when non-immune animals are born or introduced from outside the herd 

Routes of introduction:

  • purchase of new stock - PI animals, acutely infected animals, trojan horses - convalescent dam carrying PI foetus 
  • infected semen/embryos - PI bull, acutely infected bull, bull infected at puberty 
  • deer and sheep
  • breakdown of biosecurity 
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  • Desirable but expensive:
  • eliminate PIs 
  • prevent reintroduction by quarantine, or by only introducing immune animals 
  • identification of PI animals requires individual ELISA tests for Ab (negative) and Ag (positive) 
  • bulk milk tests for antibodies indicates the proportion of the herd that has seroconverted - milk tests for virus (PCR) suggests prescence of PI animals or newly introduced acute infection 
  • Compromise solution:
  • vaccinate heifers before service on an annual basis - boosters
  • live vaccines are effective but may induce MD and can infect foetuses 
  • hinders serological assessment of herd status 
  • despite large antigenic differences - immunisation of cattle with vaccines employing only BVDV1 mitigates against acute BVDV2 disease, but may not provide complete foetal protection 
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Diagnosis of BVDV

  • based on clinical history, signs and examination of reproductive records
  • history of abortions, stillborns, weak calves, and infertility problems 
  • lab diagnosis is based on virus isolation, in situ hibridisation, antigen detection, PCR and serology on paired sera 
  • BVDV1 and 2 are antigenically distinguishable using monoclonal antibodies and in neutralisation assays with antiserum 
  • specimens include faeces, urine, blood, nasal secretions, skin biopsies and post-mortem tissues
  • differential daignosis from FMDV, malignant catarrhal fever, salmonellosis, Rinderpest and Ibaraki disease 
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