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Models of infection: Porcine
Reproductive and Respiratory Syndrome
Virus (PRRSV)
Dr. Amelia Woolums
LAMS 5160
• Family Arteriviridae
– ss (+) RNA, enveloped
– genome encodes 7 proteins
• Clinical syndrome recognized in North Carolina
in mid 1980’s
• Virus isolated in Europe in 1991
– Isolated in N. America shortly thereafter
• 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??
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
• Respiratory disease
– Dyspnea and tachypnea, ill-thrift, poor growth
– Interstitial pneumonia
– Most common in grower/feeder
– Rarely, severe fatal disease in in adults
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
Courtesy Dr. D. Reeves
• NOTE that inapparent infection is not
• Infection can be prolonged (“persistent”)
– As long as 5 months post infection
– Shedding is intermittent
• Important contribution to epizootiology
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
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
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?
Effects on immune response
• Humoral:
– Rapid onset of non-neutralizing antibody
– Neutralizing response surprisingly slow (3-4
– Some in vitro evidence for antibody-enhanced
• How could antibody enhance disease?
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?
From Janeway, 1999
Cytotoxic T cell
MHC II presentation +
T Helper 1
Virus-infected host cell
Natural killer cell
A. Woolums, LAMS 5160
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
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
• Three factors have important impact on
outcome of PRRSV infection:
– Strain of infecting virus
– Host factors
– Management factors
Disease severity: influence of virus
• Genetic variability: major influence on
– Two major types: European and North American
– Only 60% concordance at genetic level
• Innumerable subtypes with varying degrees of
• Immunity to heterologous strains is incomplete
to nonexistent
Influence of viral genetic
• 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)
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)
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
• 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
• At this time, almost nothing is known about
how viral proteins relate to virulence
Disease severity: influence of host
• Many anecdotal reports of variation in
disease severity among different breeds,
• Research supports differential susceptibility
among purebreds and commercial lines
• Factors that contribute to breed-related
susceptibility not known
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 others—lead 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
Disease severity: influence of management
• Clear farm effect on PRRSV severity
– More research needed to determine relevant
– 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
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?
Disease severity: influence of
• 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
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
Disease severity: influence of management
• Other factors that impact maintenance of PRRSV-free
– Long-term, low-level infection with inapparent
– Imperfect diagnostic tests
• No test yet discovered with 100% sensitivity and 100%
• At level of discrimination needed to keep 1000’s of pigs
permanently virus-free, this matters
• Some general recommendations:
– If you’re going to live with the virus
• Maintain immunity to endogenous strains by
vaccination or planned exposure
– Ensure herd-wide immunity: don’t let
susceptible subgroups develop
• Prevent introduction of new strains that could
circumvent herd immunity
– Screen new introductions, semen, watch out
for fomites
• Some general recommendations:
– If you’re 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
В» Screening test: high sensitivity
В» Confirmatory test: suitable sensitivity, higher
• Exercise extreme vigilance to prevent introduction via
new arrivals, semen, fomites
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