Transcript Saif Presentation, Learning from SARS Workshop

ANIMAL CORONAVIRUSES:
LESSONS FOR SARS
Linda J. Saif
TGEV
Saif ©
BCoV
Food Animal Health Research Program,
Ohio Agricultural Research and Development Center,
Department of Veterinary Preventive Medicine,
The Ohio State University, Wooster, Ohio 44691, USA
Saif ©
Coronavirus Genetic Groups, Target Tissues and Diseases
Genetic Group
I
Virus
Host
Disease/ Infection Site
Respiratory
Enteric
Other
HCoV-229E
TGEV
PRCoV
PEDV
FIPV
FCoV
CCoV
HCoV-OC43
MHV
RCoV
HEV
BCoV**
human
pig
pig
pig
cat
cat
dog
human
mouse
rat
pig
cattle
X
(x)
X
III
IBV
TCoV
chicken
turkey
X
X
X
Kidney, Oviduct
IV ??
SARS
human
X
X?
Kidney?
II
X
X
X
X
X
X
X
X
??
X
X
Systemic
CNS, Systemic
Eye, GU
CNS
SARS Transmission
Droplets -
close contacts
• Households
• Hospitals (Health cares workers)
• “Superspreaders”
Airborne ?
Fecal/oral ?
Fomites ?
Masked Palm Civets
Animal host:
• Civet Cat - Reports from Hong Kong suggest masked palm civet cat may be
an animal host for SARS (Guan et al, Science Express, Sept 4, 2003)
Susceptible animal models:
• Cynomolgus macaque- (Fouchier et al, Nature 2003. 423:240)
• Pigs- Canadian report negative, but 5-6 week-old pigs used and TGEV/PRCV
serostatus undefined
• Avian species- USDA reported no transmission to SPF chickens, turkeys,
ducks or quail
Porcine Coronaviruses
Group I
PRCV
Saif ©
TGEV
Saif ©
Enteric Infections
TGEV : Transmissible Gastroenteritis Virus (1965)
Infect all age groups but highest mortality in baby pigs
PEDV : Porcine Epidemic Diarrhea Virus (1978, Europe; 1980’s, Asia) EpidemicHigh mortality in baby pigs
Endemic - Older pigs (>3 months) infected
Respiratory Infections
PRCV : Porcine Respiratory Coronavirus (1986, Europe; 1989, USA)
S gene deletion mutant of TGEV (621 – 682 bp near the N-terminus)
Infect all age groups - 1- 3-month-old, most disease
There are 2 models for respiratory and
enteric coronaviruses in animals
PRCV is a S gene deletion mutant of TGEV (same serotype)
◆TGEV infects small intestinal villous enterocytes;
Intestine
occasionally upper respiratory tract
Induces villous atrophy leading to vomiting and
diarrhea which are the main clinical signs
Lung
◆PRCV infects epithelial cells of the upper and lower
respiratory tract and a few unidentified cells in the small
intestine
Moderate or subclinical respiratory disease occurs,
but interstitial pneumonia is evident in most pigs
TGEV MILLER
Summary of genetic analysis of S gene deletion area and ORF3/3a, 3-1/3b of TGEV
and PRCV strains (Kim et al 2000)
Four Clinical Syndromes Occur
with BCoV Infections
Enteric Infections
Calf diarrhea
Diarrhea, dehydration
 Intestinal villous atrophy
Winter dysentery
Bloody diarrhea + upper
respiratory infection
 Intestinal villous atrophy
Respiratory Infections
Calf respiratory disease
Bovine respiratory disease
complex (shipping fever)
Target Age Groups
Birth to 4 wks of age
6 months to adult
2 wks to 6 months
6-9-month-old
feedlot cattle
Cough, nasolacrimal discharge, pneumonia
All BCoV isolates belong to 1 serotype (2 subtypes) and are pneumoenteric
Only point mutations occur in the S gene of BCoV-E vs BCoV-R strains
Which tissues do coronaviruses infect?
Coronavirus
Infected
Tissues
Macaque a
SARS
Pigs
TGEV-V TGEV-A (vaccine)
Cattle
PRCV
PEDV
BCoV-E
BCoV-R
Viremia
NT
-
-
+
-
NT
NT
Upper
Resp.Tract
+
+
++
++
-
+
++
Lower
Resp. Tract
+
+/-
+
+++
-
+
+++
Intestine
+/1/4
+++
+
+/-
++
(colon)
++
(colon)
++
(colon)
Intact
Pt mutations b
Deletion
Intact
(nt 214 and 655)
(621-682 nt)
S-gene
a
Fouchier, et al 2003
b
Ballesteros et al, 1997
Pt mutations c
(42 aa changes at 38 sites)
c Hasoksuz,
et al 2002
How do respiratory coronavirus infections in
animals compare to those in humans?
Respiratory Coronaviruses
Clinical signs:
Cells infected:
Lesions/
Pathology:
PRCV
Cough
± Nasolacrimal discharge
+ Fever
± Pneumonia
.
Nares, Trachea,
Alveoli, Bronchi
Alveolar macrophages
Interstitial pneumonia
Duration of shedding:
Nasal
3-10 days
Fecal
Variable, 0-a few days
BCoV-R
Cough
Nasolacrimal discharge
+ Fever
± Pneumonia
Nasal turbinates
Trachea
Bronchi, Alveoli
Interstitial emphysema
Bronchiolitis, alveolitis
5-10 days (17 days)
4-8 days (17 days)
What Factors Exacerbate Respiratory Coronavirus
Infections or Virus Shedding?
1. Aerosols
 Higher virus titers, longer shedding and more severe
respiratory disease (Van Cott et al, 1993)
2. Dose
 Higher dose = higher titer, longer shedding (Van Cott et
al, 1993)
• Pigs given 108.5 TCID50 had more severe pneumonia and
deaths than pigs exposed by contact (Jabrane et al, 1994)
3. Concurrent or sequential respiratory viral infections
 Porcine arterivirus (PRRSV) first, then PRCV after 5 days
(Hayes et al, 2000)
• Longer shedding of PRCV after dual infection
• Fecal shedding of PRCV, mainly after dual infection
• Prolonged fever, respiratory disease and reduced weight
gain after dual infection
 PRCV first, then Swine Influenza Virus 2 days later (Van
Reeth and Pensaert, 1994)
• Enhanced respiratory disease
Pig Lung tissue
Control
PRCV
PRRSV  PRCV
What Factors Exacerbate Porcine Respiratory Coronavirus
Infections or Virus Shedding?
4. Pigs infected with the Arterivirus, PRRSV or with PRCV followed by
bacterial LPS in 5 days developed more severe respiratory disease upon
LPS exposure and enhanced fever compared to pigs inoculated with each
agent alone (Laborque et al, 2002; Van Reeth et al, 2002)
5.Treatment with immunosuppressive agents: the synthetic corticosteroid,
dexamethasone
Enhanced the severity of TGEV infections (Shimizu and Shimizu, 1979)
In 1 of 4 cows inoculated with WD-BCoV-E, treatment also induced a
recurrence of fecal BCoV shedding (Tsunemitsu et al, 1999)
What Factors Exacerbate Respiratory Bovine
Coronavirus Infections or Virus Shedding?
1. Calves with lower serum Ab titers (VN titer <
400) to BCoV were more likely to be infected
and develop disease
2. Stress of shipping cattle to feedlots
3. Co-mingling cattle from different farms
4. Other concurrent respiratory infections (viruses
and bacteria)
Infectious Bronchitis Virus (IBV)
Pathogenesis
 Primary site of infection is upper respiratory tract
 Trachea and Bronchi
Virus detection
 Viremia
 Nasal secretions
 Feces and Urine
 Disease is most severe in baby chicks
Other organs infected (sites of IBV persistence with periodic nasal shedding)
 Kidneys (Nephropathogenic strains) Tissue tropism of one IBV strain altered from
respiratory to kidney tissues by serial passage in the cloaca (Uenaka et al 1998)
 Oviducts
 Intestine
Feline Infectious Peritonitis Virus(FIPV)
Pathogenesis
 Primary sites of infection are the pharyngeal, respiratory or intestinal epithelial
cells
 Two major forms:
 Effusive- peritoneal fluid accumulation
 Non effusive –fever, CNS involvement
 Viremia occurs due to infection of monocytes
 Virus is distributed throughout the body in macrophages
 Lesions: pyogranulomas with thrombosis
After antibody development: fulminant disease with
1) Immune complexes with complement, in sera and ascites fluids
2) Antibody dependent enhancement of infection
Do coronaviruses cross the species barrier?
Example: Oral inoculation of calves with enteric coronaviruses from
captive wild ruminants
Enteric coronavirus
origin:
Sambar Deer White-tailed Deer Waterbuck
Calf inoculation
Diarrhea:
Fecal shedding:
Seroconversion to BCV:
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Conclusion: Coronaviruses from wild ruminants can experimentally
infect young calves (Tsunemitsu, et al 1995)
Wild ruminants
Cattle transmission ?
Do coronaviruses cross the species barrier?
Example: Oral inoculation of poultry with BCoV-E
Turkey poults
Diarrhea:
Yes
Fecal shedding:
Yes (12 DPI)
Seroconversion to BCoV:
Yes
Chicks
No
No
NT
Conclusion: Bovine coronavirus can experimentally infect baby
turkeys (Ismail et al, 2001)
Cattle
Bird transmission ?
EMERGING ZOONOTIC VIRAL INFECTIONS

It is estimated that 75% of emerging human pathogens are zoonotic
(Murphy et al,1998 Taylor et al 2001) and that 61% of all human pathogens are
zoonotic (Woolhouse et al, 2002).

Zoonotic pathogens that infect both domestic and wildlife hosts and have
a broad host range, appear most likely to emerge (Cleaveland et al, 2001).

RNA viruses are more likely to be zoonotic than DNA viruses
(Morse,1997;Woolhouse et al, 2002).
Viral RNA replicases lack proofreading functions leading to high
mutation rates with more rapid evolution
Quasispecies exist allowing plasticity within the viral population for
adaptation to new hosts
Zoonotic RNA virus examples: Influenza, Nipah, Hendra, Rift Valley
Fever Virus, West Nile Virus, HIV, SARS CoV(?)
FACTORS INFLUENCING VIRAL EMERGENCE
Introduction of virus into a new host
“Virus traffic” via ecologic changes, demographic changes, human
activity/behavior (Lederberg et al,1992, Morse et al, 1997)
Enhanced host susceptibility (immunosuppression, preexisting health
conditions, malnutrition, poilymicrobial coinfections, etc)
Establishment and dissemination within the new host population
Increase in host movements (global travel, rural to urban migration),
density, allow for greater spread
Increasing numbers of infected individuals increase opportunity for
transmissible variants to arise
Human activity may disseminate vectors or reservoir
CONTROL OF EMERGING/ZOONOTIC
INFECTIONS
 Effective global disease surveillance and coordination of efforts
 Multidisciplinary research efforts and teams to investigate disease
outbreaks
 For zoonotic diseases, the combined efforts of biomedical and veterinary
scientists are essential, but few mechanisms currently exist to support
this type of collaboration and cooperation
CONCLUDING REMARKS
 Enteric coronaviruses alone can cause fatal infections in seronegative young
animals; respiratory coronavirus infections are more often fatal in adults
when combined with other factors (shipping fever in cattle)
 Factors that exacerbate respiratory coronavirus infections in animals include
high exposure doses, respiratory coinfections (viruses, LPS), treatment with
corticosteroids
 Knowledge of SARS pathogenesis (using appropriate animal models) is
extremely important to design effective vaccines
 There are no vaccines to prevent respiratory coronavirus infections except
for IBV infections in chickens
 Vaccination for IBV (killed or live) is complicated by the existence of multiple
serotypes/subtypes
 Only short-term protection is needed because of the short life span of chickens
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