Virus Diseases of Complex 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

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

• 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

• 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

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

• 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

• 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

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

• 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)

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

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)

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)

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 

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

• 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..

• 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 

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 

• 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

• 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

• 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

• 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)

• 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