Models of infection: Porcine Reproductive and Respiratory Syndrome Virus (PRRSV)

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Models of infection Porcine Reproductive and
Respiratory Syndrome Virus (PRRSV)

• Dr. Amelia Woolums
• LAMS 5160

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PRRSV

• Family Arteriviridae
• ss () RNA, enveloped
• genome encodes 7 proteins
• Clinical syndrome recognized in North Carolina in
  mid 1980s
• Virus isolated in Europe in 1991
• Isolated in N. America shortly thereafter

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PRRSV

• Already significant genetic variability when
  European and NA types identified
• Mathematical modeling suggests virus first
  appeared 1980
• Jumped from another species?
• Other family members
• equine arteritis virus (EAV)
• LDH-elevating virus (LDV)
• possible source of PRRSV??

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PRRSV, clinical signs

• Reproductive problems
• late gestation most common
• litters with normal, weak, stillborn, and mummies
• anorexia, agalactia in sows
• early gestation losses possible abortions,
  return to service
• Respiratory disease
• Dyspnea and tachypnea, ill-thrift, poor growth
• Interstitial pneumonia
• Most common in grower/feeder
• Rarely, severe fatal disease in in adults

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PRRSV, clinical signs

• Cutaneous signs possible
• Hyperemia or cyanosis of extremities
• Neuro signs in sows rarely
• Repro, respiratory, and cutaneous signs very
  similar to EAV in horses

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http//www.elsenburg.com/vets/prrs
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http//www.elsenburg.com/vets/prrs
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Courtesy Dr. D. Reeves
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• NOTE that inapparent infection is not unusual
• Infection can be prolonged (persistent)
• As long as 5 months post infection
• Shedding is intermittent
• Important contribution to epizootiology

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Pathogenic mechanisms

• Virus targets macrophages
• Alveolar macrophages, tissue macrophages
• Primary sites in acute disease
• Lung
• Lymphoid tissue lymphadenopathy common
• Many other sites possible kidney, spleen, heart,
  thymus, skin, reproductive tract, nervous system
• In chronic phase, virus found in peripheral lymph
  nodes, TONSILS

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• Consider how could preferential targeting of
  macrophages contribute to disease?
• Decreased (or increased?) production of
  proinflammatory cytokines (TNF-a, IL-1)
• Decreased APC activity decreased activation of
  CD4 TH cells
• Decreased clearance of virus and cell debris

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PRRSV, effects on macrophages

• Direct killing of macrophages
• Decreased production of TNF-a
• as compared to influenza, other viruses
• Decreased phagocytosis
• Induction of apoptosis of bystanders
• Possibly related to dysfunctional cytokine or
  costimulatory molecule expression by MP?

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Effects on immune response

• Humoral
• Rapid onset of non-neutralizing antibody
• Neutralizing response surprisingly slow (3-4 wks)
• Some in vitro evidence for antibody-enhanced
  disease
• How could antibody enhance disease?

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Effects on immune response

• Cell-mediated
• T cell responses following vaccination or
  infection are slow and weak
• IFN-a production actively suppressed
• Cells exposed to PRRSV then TGE virus (strong
  IFN-a inducer) no IFN-a
• Why does IFN-a matter?

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A. Woolums, LAMS 5160
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Effects on immune response

• PRRSV suppresses TH1 response
• Decreased IFN-a
• Decreased TNF-a
• Increased IL-10
• Suppresses TH1 response
• Net effect poor response to intracellular
  pathogen

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PRRSV, outcome of infection

• Outcome of PRRSV infection in a herd of pigs is
  unpredictable
• Why some infected herds apparently suffer no ill
  effects while others are constantly battling
  clinical PRRS is not known
• Zimmerman, 2003

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• Three factors have important impact on outcome of
  PRRSV infection
• Strain of infecting virus
• Host factors
• Management factors

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Disease severity influence of virus

• Genetic variability major influence on
  pathogenesis
• Two major types European and North American
• Only 60 concordance at genetic level
• Innumerable subtypes with varying degrees of
  relatedness
• Immunity to heterologous strains is incomplete to
  nonexistent

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Influence of viral genetic variability

• PRRSV exists as quasispecies
• Genetic variation occurs between farms, among
  pigs, and WITHIN individual pigs
• Farm level diversity (nucleotide) 93
• Among pigs 4
• Within a given pig 3
• No two pigs on the same farm had identical PRRSV
• Multiple variants coexist in individual animals
• 
  (Goldberg et al, 2003)

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Influence of viral genetic variability

• PRRSV mutates at an unusually rapid rate, even
  for an RNA virus
• 10-2/amino acid site/year, as compared to 10-3
  to 10-5 for HIV, hepatitis C virus
• Data suggests this is due to more rapid
  replication, rather than higher error rate, than
  other RNA viruses
• 
  (Hanada et al, 2005)

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• How does the rapid generation of genetic variants
  contribute to the disease caused by PRRSV?
• Frequent opportunity for virus to evade host
  immune response
• New variants could lead to disease in susceptible
  subgroups within a supposedly resistant herd
• Theoretically, persistent virus could outstrip
  host immunity and lead to recurrent disease in
  previously infected individual
• Very difficult to come up vaccines effective in
  every situation

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• Viral strain impacts virulence
• Genetic variability could allow opportunity for
  improved virulence how?
• Change in receptor better attachment/invasion?
• Change in proteins that impair host immunity?
• Change in proteins that promote inter-pig
  transmission?
• At this time, almost nothing is known about how
  viral proteins relate to virulence

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Disease severity influence of host

• Many anecdotal reports of variation in disease
  severity among different breeds, families
• Research supports differential susceptibility
  among purebreds and commercial lines
• Factors that contribute to breed-related
  susceptibility not known

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Disease severity influence of host

• Coinfection with other agents makes disease due
  to PRRSV worse
• Influenza, porcine circovirus-2, TGE, Mycoplasma
  hyopneumoniae, Strep. suis among otherslead to
  enhanced PRRSV
• Does PRRSV-induced immunosuppression enhance
  secondary disease? Data mixed
• Likely important in at least some cases
• PRRSV M. hyopneumoniae currently considered
  leading cause of respiratory disease in
  growing/finishing pigs

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Disease severity influence of management

• Clear farm effect on PRRSV severity
• More research needed to determine relevant
  factors
• SIZE of farm consistently associated with PRRSV
  problems
• Larger farms more likely to have disease,
  persistent/recurrent infection
• Smaller farms less problems, even if no efforts
  made to prevent disease

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Disease severity influence of management

• Although some farms can have inapparent
  infection, overall, PRRSV is associated with
  decreased productivity
• Choice for management try to eradicate, or live
  with it?

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Disease severity influence of management

• Problem strategies that have worked to maintain
  herds free of other pathogens have not worked
  well for PRRSV
• Herds cleared of PRRSV infection can become
  reinfected despite all efforts to prevent
  reintroduction

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Disease severity influence of management

• Important sources of infection
• New introductions
• Infected semen
• Possible sources of infection
• Fomites trucks, boots, coolers (for transporting
  semen), lunchboxes (!)
• Fomite transport a bigger problem when cool (34
  F)
• Flies, mosquitoes, mallard ducks
• Airborne from neighboring farms

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Disease severity influence of management

• Other factors that impact maintenance of
  PRRSV-free status
• Long-term, low-level infection with inapparent
  shedding
• Imperfect diagnostic tests
• No test yet discovered with 100 sensitivity and
  100 specificity
• At level of discrimination needed to keep 1000s
  of pigs permanently virus-free, this matters

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• Some general recommendations
• If youre going to live with the virus
• Maintain immunity to endogenous strains by
  vaccination or planned exposure
• Ensure herd-wide immunity dont let susceptible
  subgroups develop
• Prevent introduction of new strains that could
  circumvent herd immunity
• Screen new introductions, semen, watch out for
  fomites

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• Some general recommendations
• If youre going to try to be PRRSV-free
• Consider depopulation/repopulation
• Undertake regular serologic and virologic testing
  to identify and segregate/remove infected animals
• Once infected animals cleared, regularly monitor
• Consider using multiple diagnostic tests to
  maximize sensitivity/specificity
• Screening test high sensitivity
• Confirmatory test suitable sensitivity, higher
  specificity
• Exercise extreme vigilance to prevent
  introduction via new arrivals, semen, fomites