Virus Diseases of Complex Aetiology

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Multi-factorial aetiology

develop as a result of complex interactions between environmental factors, host factors, and pathogens 

  • environmental factors 
    • transport, commingling, crowding, and inadequate ventilation 
  • stressors of immune and non-immune systems 
    • weaning, diet, transport 
  • often more than one pathogen present 
    • crowding and poor ventilation can enhance transmission
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Canine Infectious Tracheobronchitis (ITB)

aka Kennel Cough 

  • Acute, highly contagious respiratory infection
  • Common in 'high density’ dog populations where there is mixing 
    •   Kennels, veterinary hospitals, pet shops, breeder
  •  Multiple pathogens: Canine parainfluenza virus-2, Canine adenovirus-2, Bordetella bronchiseptica
  • Direct contact, aerosol or mechanical transmission
  • Common in puppies at weaning
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Pathogens in Kennel Cough

  • Individual infection causes mild disease
  • Multiple infection increases disease severity and duration
    • Can lead to fatal bronchopneumonia
  • Incubation 3-10 d
  • Clinical signs 10-20 d: (fever), sneezing, coughing fits, nasal discharge, vomiting/gagging after exercise or pressure on the trachea (collar), expectoration of mucous
  • Recurrence of clinical signs with exercise/stress
  • Attenuated vaccines for some of the causative agent 
    • B. bronchiseptica, CPiV-2, CAV-2  
    • not 100% protective
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Pathogenesis Kennel Cough (1)

  • Pathogens colonise epithelium of nasal cavity, larynx, trachea, bronchi, bronchioles, pulmonary interstitium. Primary infection causes damage to epithelium and allows secondary infections to establish. 
  • Primary infection 
    • Canine parainfluenza-2 
    • Canine adenovirus-2 
    • Bordetella bronchiseptica
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Pathogenesis Kennel Cough (2)

Secondary, opportunistic infection 

  • Canine distemper virus (CDV) 
  • Canine herpesvirus (CHV, CaHV1) 
  • Canine adenovirus-1 (CAV-1,CHV) 
  • Canine reovirus 
  • Canine pneumovirus 
  • Canine respiratory coronavirus (CRCoV) 
  • Canine influenza virus 
  • Streptococcus species (S. equi subspecies zooepidemicus) 
  • Pasteurella multocida 
  • Pseudomonas species 
  • Mycoplasma species
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Primary infections

  • Primary viral infection (CPiV-2, CAV-2) 
    • Viral damage to epithelium 
    • Interference with immune responses 
      • Parainfluenza virus V proteins inhibit interferon responses 
      • Adenoviruses have multiple immune evasion mechanisms 
  • Primary B. bronchiseptica infection 
    • Commensal or pathogen 
    • Regulates its virulence state (Bvg system) 
    • Grows on and infects ciliated epithelium causing ciliostasis 
    • Releases toxins eg decrease neutrophil function - phagocytosis inhibited
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Respiratory Syndrome of Calves, Enzoonotic pneumon

  • Similar to shipping fever - bovine respiratory disease complex 
  • Usually calves less than 6 mo old, peak 2-10 week old (decreased maternal immunity) 
  • Winter peaks - humidity, temperature changes 
  • Up to 100% morbidity and 20% fatality 
  • Production losses Fever, coughing, nasal discharges, conjunctivitis 
  • Transmission by aerosol and direct contact
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Resp. syndrome calves (2)

Susceptibility:

  • Waning maternal immunity, mixing of animals 
    • Poor immunity 
      • colostral uptake poor - reduced maternal Ab protection 
      • Dietary deficiency eg mineral, vitamin 
      • high levels of ammonia/CO2 – increased endogenous corticosteroids 
    • Stress 
      • Environment and management 
      • Inadequate ventilation – increases transmission 
      • Poor nutrition eg poor milk replacements 
      • Adding new calves to established groups/older animals
      • Crowding
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Pathogenesis Respiratory Syndrome

  • Primary URT viral/mycoplasma infection then secondary bacterial infection of LRT 
  • Primary Virus infection 
    • bovine respiratory syncytial virus (BRSV) 
    • parainfluenza virus-3 (PiV-3) 
    • bovine viral diarrhoea virus (BVDV) 
  • Virus infection causes 
    • Direct damage to respiratory tract epithelium 
    • Immunosuppression 
  • Secondary bacterial infection 
    • Pasteurella multocida, Histophilus somni, Mycoplasma bovis - may be primary 
    • Bacteria often commensal in URT, increased replication and seeding to LRT, impaired clearance and colonisation leading to bronchopneumonia (fibrotic)
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Damage and Immunosuppression by viruses (1)

Bovine Respiratory Syncytial Virus (BRSV) 

  • Infection of ciliated epithelial cells, type II pneumocytes 
    • non-cytopathic in culture 
    • necrosis and apoptosis of epithelial cells, syncytial formation in vivo 
  • Damages cilia  
  • Induces inflammatory response (F protein/TLR4 -> NFkB activation) 
  • Antagonises IFN responses (NS2 protein) - tip to inflammation rather than protection 
  • Virokinin (from F protein = tachykinin) - smooth muscle contraction - bronchoconstriction? 
  • Leukocytes more susceptible to M. haemolytica leukotoxin 
  • Reduced responsiveness of mononuclear cells
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Damage and Immunosuppression by viruses (2)

Bovine parainfluenza virus type 3 (PI-3) 

  • Infection of epithelial cells of URT and LRT 
  • Damages cilia 
  • Decreases alveolar macrophage function (FcR expression, phagocytosis, microbidical activity) 

Bovine Viral Diarrhoea Virus (BVDV) 

  • Diarrhoea, erosive lesions of the GI tract, mild pneumonia 
  • Targets lymphocytes and macrophages - Leukopenia  
  • Decreased proliferation and cytokine responses of leukocytes.  2 protein products N(pro) promotes IRF3 degradation and E(rns) inhibits type I IFN induction ie both reduce type I IFN production. 
  • Neutrophil function decreased (ADCC, bactericidal activity)
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Secondary Bacterial Infection (1)

Pasteurella multocida 

  • Gram negative coccobacillus 
  • Ubiquitous in ruminants, commensal in nasopharynx 
  • Opportunistic pathogen 
  • Need prolonged impaired defense mechanisms for lung colonisation 
  • Fibrinous pleuropneumonia 
  • Less severe disease than M. haemolytica 
  • Vaccines available

(Respiratory syndrome of calves)

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Secondary Bacterial Infection (2)

Mycoplasma bovis

  • Respiratory disease, otitis media, mastitis, arthritis 
  • May be primary or secondary infection in respiratory syndrome 
  • Seroconversion to Mycoplasma bovis found in animals with increased risk of respiratory syndrome 
    • Isolated from cattle with respiratory disease and found within lesions 
    • Isolated from disease free animals 
  • URT mucosa and mammary gland most important sites for shedding 
  • After exposure (udder-udder, respiratory) becomes transient systemic infection 
  • proportion of animals become chronic intermittent shedders persistence in the population 
  • Stress increases rates nasal shedding transport, mixing, cold stress 
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Secondary Bacterial Infection (3)

Mycoplasma bovis cont.

  • Molecules involved in Lack cell wall, have variable surface proteins (Vsps) in membrane 
    • adherence 
    • antigenic variation 
    • invasion 
    • immunomodulation 
    • biofilm formation 
    • production of toxic metabolites eg phosholipases, hydrogen peroxide 
  • Inappropriate macrophage activation - inflammation, neutrophil recruitment 
  • Pneumonia - immunopathological inflammation - lymphocytes, cytokines 
  • Bacterial co-infection common eg M. haemolytica 
  • No evidence vaccination protective
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Other pathogens involved (Respiratory Syndrome in

  • BoHV-1
  • Bovine respiratory coronavirus
  • bovine adenovirus
  • Mannheimia haemolytica - fibrinosuppurative pneumonia 
  • Histophilus somni (Haemophilus somnus) 
    • Lipooligosaccharide (LOS) - like LPS
  • Mycoplasma dispar
  • Ureaplasma spp
  • Arcanobacterium pyogenes
  • others..
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Shipping Fever, bovine respiratory disease complex

  • bronchopneumonia usually precipitated when calves move to feedlots - mixing from disparate sources, clinical signs 7-10 days after entry to lot
  • pathogens very simiar to respiratory syndrome of calves - more predominance of 
    • BoHV-1 - lytic infection, immunosuppressive (neutrophil chemotaxis, lymphocyte activation, increased binding leukotoxin - increase apoptosis), latency 
    • Mannheimia haemolytica 
  • stressors 
    • transportation of long distances - dehydration, starvation, exhaustion, extremee temp changes 
    • multiple vaccinations, surgery
    • change to high energy diet 
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PCV-2 associated disease PCVD

Porcine circovirus type 2, PCV-2 

  • Post weaning multisystemic wasting syndrome PMWS
  • Porcine dermatitis and nephropathy syndrome PDNS
  • Porcine respiratory disease complex 
  • reproductive disorders 
  • prenatal myocarditis 
  • congenital tremors 
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History of PMWS

  • first diagnosed in Canada in 1991 (retrospective 1985), UK in 1999
  • newly emerging virus
    • first isolated PCV-2 in 1997
    • serologically dissimilar to PCV-1
  • PCV-2 ubiquitous world-wide prior to emergence of disease 
  • possible reasons for emergence of disease?
    • virus adaptation
    • management/environmental effect
    • host genetics
    • another trigger factor
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PCV-2

  • circovirus - stable, non-enveloped virion 
  • circular ssDNA virus, 1.7Kb, 3 ORFs, splicing increases number of proteins produced 
  • Requires host DNA pol for replication 
  • PCV-2 infects lymphocytes, especially T lymphocytes
  • antigen found in macrophages probably from phagocytosis
  • evolution over time -PCV-2a,2b,2c variants based on ORF-2 (capsid) sequence
    • 2a - predominant globally prior to epizoonotic PCDV but present in early cases of PCDV in Europe
    • 2b - displaced PCV2a as predominant strain during epizoonotic period
    • 2c - variants described only in Denmark in 1980/90s
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PMWS

  • Post-weaning mortality
  • wasting - aged 6-14 weeks
  • anaemia, enteritis, hepatitis, pulmonary change 
  • enlarged lymph nodes
  • histopathologic changes in lymph node 
    • loss of lymphocytes 
    • histiocytic infiltration 
    • PCV-2 antigen by immunostain 
  • immunosuppression
  • similar to porcine reproductive and respiratory syndrome disease 
  • morbidity 3-50%, mortality <40% - affected by health status of herd
  • no validated methods for predicting susceptibility or maintaining exclusion of disease 
  • porcine circovirus type 2 is central to disease - not all PCV-2 +ve pigs get sick
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PCVD - PCV-2 infection

  • Immune dysregulation 
    • immunosuppression
      • depletion of circulating lymphocyte lineages (B, CD4, CD4/8, NK)
      • macrophage function affected 
        • microbicidal activity reduced 
        • inflammatory response increased (TNFalpha, IL-8)
      • secondary disease common (Glasser's, Salmonellosis)
    • hypersensitivity 
      • immune complex disease
      • porcine dermatitis and nephropathy syndrome (PDNS)
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Porcine dermatitis and nephropathy syndrome PDNS

  • ventrocaudal skin lesions
  • low morbidity (importance of differential diagnosis)
  • type III hypersensitivity dermonecrosis 
  • immune complex mediated glomerulopathy
  • generalised lymphadenopathy and oedema in severe cases 

PCVD - porcine respiratory disease complex 

  • mixed infection with PRRSV, Swine flu virus, Mycoplasma hypopneumoniae

PCVD - PCV-2 reproductive disease 

  • abortion, still birth, low viability, low litter size 
  • naive dam exposed to PCV-2 at insemination or during pregnancy 
  • uncommon
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