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ANIMAL CORONAVIRUSES: LESSONS FOR SARS Linda J. Saif Food Animal Health Research Program, Ohio Agricultural Research and Development Center, Department.

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Presentation on theme: "ANIMAL CORONAVIRUSES: LESSONS FOR SARS Linda J. Saif Food Animal Health Research Program, Ohio Agricultural Research and Development Center, Department."— Presentation transcript:

1 ANIMAL CORONAVIRUSES: LESSONS FOR SARS Linda J. Saif 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 © TGEV Saif © BCoV

2 Coronavirus Genetic Groups, Target Tissues and Diseases Genetic Group VirusHost Disease/ Infection Site Respiratory Enteric Other I HCoV-229E human X TGEV pig (x) X PRCoV pig X PEDV pig X FIPV cat X X Systemic FCoV cat X CCoV dog X II HCoV-OC43 human X ?? MHV mouse CNS, Systemic RCoV rat Eye, GU HEV pig X CNS BCoV** cattle X X III IBV chicken X X Kidney, Oviduct TCoV turkey X IV ?? SARS human X X ? Kidney?

3 SARS Transmission Droplets - close contacts Households Hospitals (Health cares workers) “Superspreaders” Airborne ? Fecal/oral ? Fomites ? 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 :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 Masked Palm Civets

4 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) Epidemic- High 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 month-old, most disease Porcine Coronaviruses Group I Saif © PRCV Saif © TGEV

5 There are 2 models for respiratory and enteric coronaviruses in animals ◆ TGEV infects small intestinal villous enterocytes; occasionally upper respiratory tract  Induces villous atrophy leading to vomiting and diarrhea which are the main clinical signs Intestine Lung PRCV is a S gene deletion mutant of TGEV (same serotype) ◆ 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

6 Summary of genetic analysis of S gene deletion area and ORF3/3a, 3-1/3b of TGEV and PRCV strains (Kim et al 2000) TGEV MILLER TGEV MILLER

7 Four Clinical Syndromes Occur with BCoV Infections Enteric Infections Target Age Groups Calf diarrhea Diarrhea, dehydration  Intestinal villous atrophy Birth to 4 wks of age Winter dysentery Bloody diarrhea + upper 6 months to adult respiratory infection  Intestinal villous atrophy Respiratory Infections Calf respiratory disease 2 wks to 6 months Bovine respiratory disease 6-9-month-old complex (shipping fever) 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

8 Which tissues do coronaviruses infect? Coronavirus Infected Tissues Macaque a PigsCattle SARS TGEV-V TGEV-A (vaccine) PRCVPEDVBCoV-EBCoV-R ViremiaNT--+- Upper Resp.Tract Lower Resp. Tract ++/ Intestine+/- 1/ /-++ (colon) ++ (colon) ++ (colon) S-geneIntactPt mutations b (nt 214 and 655) Deletion ( nt) IntactPt mutations c (42 aa changes at 38 sites) a Fouchier, et al 2003 b Ballesteros et al, 1997 c Hasoksuz, et al 2002

9 How do respiratory coronavirus infections in animals compare to those in humans? Respiratory Coronaviruses PRCVBCoV-R Clinical signs: CoughCough ± Nasolacrimal discharge Nasolacrimal discharge + Fever + Fever ± Pneumonia ± Pneumonia. Cells infected: Nares, Trachea, Nasal turbinates Alveoli, Bronchi Trachea Alveolar macrophages Bronchi, Alveoli Lesions/ Pathology:Interstitial pneumonia Interstitial emphysema Bronchiolitis, alveolitis Duration of shedding: Nasal 3-10 days 5-10 days (17 days) Fecal Variable, 0-a few days 4-8 days (17 days)

10 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 TCID 50 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 PRRSV  PRCV PRCV Control Pig Lung tissue

11 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)

12 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)

13 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

14 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

15 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: Yes Yes Yes Fecal shedding: Yes Yes Yes Seroconversion to BCV: Yes Yes Yes Conclusion:Coronaviruses from wild ruminants can experimentally infect young calves (Tsunemitsu, et al 1995) Wild ruminants Cattle transmission ?

16 Do coronaviruses cross the species barrier? Example: Oral inoculation of poultry with BCoV-E Turkey poults Chicks Diarrhea: Yes No Fecal shedding: Yes (12 DPI) No Seroconversion to BCoV: Yes NT Conclusion:Bovine coronavirus can experimentally infect baby turkeys (Ismail et al, 2001) Cattle Bird transmission ?

17 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(?)

18 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

19 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

20 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

21 REFERENCES Ballesteros, M.L., C.M. Sanchez, L. Enjuanes Two amino acid changes at the N-terminal of the transmissible gastroenteritis coronavirus pike protein result in the loss of enteric tropism. Virology 227: Cavanagh, D., and S.A. Naqi Infectious Bronchitis. In Diseases of Swine (Y.M. Saif et al., eds) 11th Ed. Iowa State Press, Ames, Iowa. Cho, K.O., A. Hoet, S.C. Loerch, T.E. Wittum and L.J. Saif Evaluation of concurrent shedding of bovine coronavirus via the respiratory and enteric route in feedlot cattle. Am. J. Vet. Res. 62: Cho, K.O., P.R. Nielsen, K.O. Chang, S. Lathrop and L.J. Saif Cross-protection studies of respiratory, calf diarrhea and winter dysentery coronavirus strains in calves and RT-PCR and nested PCR for their detection. Arch. Virol. 146: El-Kanawati, Z. R., H. Tsunemitsu, D. R. Smith and L. J. Saif Infection and cross-protection studies of winter dysentery and calf diarrhea bovine coronavirus strains in colostrum-deprived and gnotobiotic calves. Am. J. Vet. Res. 57: Fouchier, R.A.M., T. Kuiken, M. Schutten, G. van Amerongen, G.J.J. van Doornum, B.G. van den Hoogen, M. Peiris, W. Lim, K. Stohr, A.D.M.E. Osterhaus Koch postulates fulfilled for SARS virus. Nature 423:240. Guan,Y, et al Isolation and characterization of viruses related to the SARS coronavirus from animals in Southern China. Science Express, Sept 4,2003 Hasoksuz, M., S. Sreevatsan, K.O. Cho, A.E. Hoet and L.J. Saif Molecular analysis of the S1 subunit of the spike glycoprotein of respiratory and enteric bovine coronavirus isolates. Virus Res. 84: Hayes, J., K. Sestak, G. Myers, L. Kim, P. Stromberg, B. Byrum, R. Mohan, and L.J. Saif. Evaluation of dual infection of nursery pigs with U.S. strains of porcine reproductive and respiratory syndrome virus and porcine respiratory coronavirus. Proc. VIIth International Symposium on Nidoviruses (Corona and Arteriviruses), Lake Harmony, PA, May 20-25, Ismail, M.M., K.O Cho, L.A. Ward, L.J. Saif and Y.M. Saif Experimental bovine coronavirus in turkey poults and young chickens. Avian Dis. 45: Jabrane, A., C. Girard, Y. Elazhary Pathogenicity of porcine respiratory coronavirus isolated in Quebec. Can. Vet. J. 35:86-92.

22 REFERENCES Kim, L., J. Hayes, P. Lewis, A.V. Parwani, K.O. Chang and L.J. Saif Molecular characterization and pathogenesis of transmissible gastroenteritis coronavirus (TGEV) and porcine respiratory coronavirus (PRCV) field isolates co-circulating in a swine herd. Arch. Virol. 145: Lathrop, S.L., T.E. Wittum, S.C. Loerch, L.J. Perino and L.J. Saif Antibody titers against bovine coronavirus and shedding of the virus via the respiratory tract in feedlot cattle. Am. J. Vet. Res. 61: Labarque, G., K. Van Reeth, S. Van Gucht, H. Nauwynck, M. Pensaert Porcine reproductive-respiratory syndrome virus infection predisposes pigs for respiratory signs upon exposure to bacterial lipopolysaccharide. Vet. Microbiol. 88:1-12. Laude, H., K.V. Reeth, M. Pensaert Porcine respiratory coronavirus: molecular features and virus-host interactions. Vet. Res. 24: Lederberg, J., R.E. Shope, S.C. Oaks Emerging infections—Microbial threats to health in the US. Institute of Medicine, National Academies Press. Morse,S.S The public health threat of emerging viral disease. Am Soc Nutr Sci. 127:951S-957S. Olsen, C.W A review of feline infectious peritonitis virus: molecular biology, immunopathogenesis, clinical aspects, and vaccination. Vet. Microbiol. 36:1-37. Pensaert, M.B Porcine Epidemic Diarrhea. In Diseases of Swine 8th Ed. (Straw, B.E., et al., eds) Iowa State Univ. Press. Ames, IA, pp Saif, L. J. and Heckert, R. A Enteric coronaviruses. In Viral Diarrheas of Man and Animals, (L. J. Saif and K. W. Theil, eds), CRC Press, Boca Raton, Florida, pp Saif, L. J. and R. Wesley Transmissible gastroenteritis virus. In Diseases of Swine (B. Straw et al., eds) 8th Ed. Iowa State Univ. Press, Ames, Iowa. Saif, L.J Coronaviruses: Update on diagnosis, pathogenesis and control of bovine coronavirus-associated calf diarrhea, winter dysentery and shipping fever. Proc. Iowa Veterinary Medical Association Mtg., Iowa State University, College of Veterinary Medicine, Ames, IA, September 12, Sestak, K., R.K. Meister, J.R. Hayes, L. Kim, P.A. Lewis, G. Myers and L.J. Saif Active immunity and T-cell populations in pigs intraperitoneally inoculated with baculovirus-expressed transmissible gastroenteritis virus structural proteins. Vet. Immunol. Immunopath.70:

23 REFERENCES Sestak, K. and L.J. Saif Porcine coronaviruses. In Trends in Emerging Viral Infections of Swine (J.J. Zimmerman, et al, eds.) Iowa State Univ. Press, Ames, Iowa (In press). Shimizu, M. and Y. Shimizu Effects of ambient temperatures on clinical and immune responses of pigs infected with transmissible gastroenteritis virus. Vet. Microbiol. 4: Shoup, D. I., D. J. Jackwood, and L. J. Saif Active and passive immune responses to transmissible gastroenteritis virus (TGEV) in swine inoculated with recombinant baculovirus-expressed TGEV spike (S) glycoprotein vaccines. Am. J. Vet. Res. 58: Tsunemitsu, H., H. Reed, Z. El-Kanawati, D. Smith, and L. J. Saif Isolation of coronaviruses antigenically indistinguishable from bovine coronavirus from a Sambar and white tailed deer and waterbuck with diarrhea. J. Clin. Microbiol. 33: Tsunemitsu, H., Z. El-Kanawati, D. Smith, H. Reed, and L. J. Saif Isolation of coronaviruses antigenically indistinguishable from bovine coronavirus from wild ruminants with diarrhea. J. Clin. Microbiol. 33: Van Cott, J. L., T. A. Brim, R. A. Simkins and L. J. Saif Antibody-secreting cells to transmissible gastroenteritis virus and porcine respiratory coronavirus in gut- and bronchus-associated lymphoid tissues of neonatal pigs. J. Immunol. 150: Van Cott, J., T. Brim, J. Lunney, and L. J. Saif Contribution of antibody secreting cells induced in mucosal lymphoid tissues of pigs inoculated with respiratory or enteric strains of coronavirus to immunity against enteric coronavirus challenge. J. Immunol. 152: Van Reeth, K. and M. Pensaert Porcine respiratory coronavirus-medicated interference against influenza virus replication in the respiratory tract of feeder pigs. Am. J. Vet. Res. 55: Van Reeth, K., S. Van Gucht and M. Pensaert In vivo studies on cytokine involvement during acute viral respiratory disease of swine: troublesome but rewarding. Vet. Immunol. Immunopath. 87: Woolhouse, M.E.J Population biology of emerging and re-emerging pathogens. Trends in Microbiol. 10: S3-S7


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