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Flavi and Pestiviruses

Flavi and Pestiviruses

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Flavi and Pestiviruses

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  1. Flavi and Pestiviruses October 12, 2010

  2. BVD, Hog cholera, Border disease Pestiviruses Flaviviridae Flaviviruses Hepacviruses Hepatitis C virus Yellow fever Japanese encephalitis St. Louis encephalitis Dengue West Nile virus (arthropods, biological vectors)

  3. West Nile Outbreaks • Israel - 1951-1954, 1957 • South Africa - 1974 • Romania – 1996 • Italy – 1998, 2008 • Russia - 1999 (human) • United States –1999-2009 (equine, human) • Canada - 2001-2009 (equine, human) • Israel – 1998, 2000 (human) • France (Rhine delta) - 2000 (equine)

  4. return from south late summer and fall spring early summer overwinter or eggs dead-end hosts amplification in birds

  5. Saskatchewan mosquito species shown to be capable of transmitting WNV • Aedesvexans (spring to fall) • Ochlerotatusflavescens, spencerii(July-August) • Culexrestuans*, tarsalis*(July-August) • Culiseta inornata* • Coquillettidiaperturbans

  6. How does the virus overwinter and spread? • migratory birds? • overwintering mosquitos? • bird to bird transmission? • Komar et al. EID March 2003

  7. in the mosquito 3. virus leaks from gut and infects salivary glands 4. virus released in saliva during feeding 2. virus multiplies in gut epithelial cells 1. virus ingested with blood meal (sufficient amount of virus must be ingested - > 105 infectious units/ml)

  8. in mammals virus transmitted in mosquito saliva during probing virus deposited in extra vascular tissue replication in skin and lymph nodes “flu” like symptoms amplification in extra-neural tissues viremia (secretion in milk) PCR viremia terminated by immune response crosses blood/brain barrier (repl’n in vascular endothelium, exacerbated by concurrent infections) IgM, inflammation perivascular infiltration (plasma cells and macs), cerebral edema. “neurological” signs viral damage to neurons and glia or dysfunction CSF IgM, pleocytosis, PCR

  9. equine cases of WNV neurological disease • Ataxia 86% • Depression 51% • Hind limb weakness 49% • Difficulty or inability to rise 46% • Muscle tremors 41% • Fever only 24% • Differentials: • rabies, EHV 1, EEE, WEE, botulism • 10% to 50% of horses with neurological signs die

  10. clinical signs in people • most asymptomatic • fever, “flu” like symptoms (fatigue, anorexia, nausea, vomiting, arthralgia, rash, lymphadenopathy) • encephalitis, meningoencephalitis - ataxia, painful eyes, seizures, change in mental status (confusion) case fatality rate in hospitalized patients - 10-12% risk factor for severe disease (age 50-60 yr are 10 times and >80 yr are more than 40 times likely) Petersen and Margin, WN virus: a primer for the clinician 2002. Ann Int med 137:173

  11. unusual cases in USA • infant infected through breast milk • 2 people infected through blood transfusion • 2 laboratory workers while dissecting infected animals

  12. the Canadian experience • 2000 - 2,288 birds examined, 185 tested - no positives • 2001 - 2,807 bird carcasses from NF to Sask tested • 128 WNV infected birds from 12 health dist. in Ontario • no disease in horses or humans

  13. human cases 2003-2005 May June July Aug Sept Oct

  14. http://www.phac-aspc.gc.ca/wnv-vwn/mon-hmnsurv-archive-eng.phphttp://www.phac-aspc.gc.ca/wnv-vwn/mon-hmnsurv-archive-eng.php

  15. http://www.phac-aspc.gc.ca/wnv-vwn/mon-hmnsurv-eng.php

  16. West Nile virus in domestic birds • geese • ducks • chickens and turkeys • ostriches, emus

  17. testing for WNV - serology samples from 45 horses, Virden Manitoba (Aug-Sept, 2002) strong + cont weak + cont IgM capture ELISA PDS immunol. lab

  18. vaccines Fort Dodge Intervet – PreveNile Live Flavivirus chimera

  19. West Nile Virus – Common Client Questions • Should we vaccinate our horse – is it safe and does it work? • Can I catch WNV from a horse? • What signs might a horse show early on? • Is there a treatment? • What can we do to limit the risk to our horse? • Can our other pets get it? • When should we vaccinate our horses?

  20. Systemic haemorrhagic disease - pigs (USA) Enteric disease - calves (USA) Congenital, neurological “hairy-shakers” (England/Wales) Pestiviruses HCV 1940s BVDV BDV

  21. Flaviviruses Flaviviruses Japanese encephalitis Louping ill Hepatitis C Pestiviruses St. Louis encephalitis Murray Valley Dengue Yellow fever West Nile Pestiviruses of Artydactyla hog cholera (HCV) bovine viral diarrhoea (BVDV) border disease (BDV) Wide host range (camelids, deer etc)

  22. BVDV genome and gene products nonstructural structural UTR gp53 p125 (p54+p80) Regions that show the most variation

  23. Biotypes of BVDV Based on effect on cells in tissue-culture NON-cytopathic (natural state) Cytopathic (mutant)

  24. CP vs NCP – genetic differences nonstructural structural UTR p125 (p54+p80)

  25. Non-cytopathic Implications for vaccines and research Cytopathic Mucosal disease Biotypes - implications

  26. BVDV-1 BVDV-2 nonstructural structural UTR BVDV “types” Not different serotypes!! Based on: 1. sequence differences In non-translated region of genome Does not imply differences in pathogenicity 2. Antigenic differences

  27. Antigenic differences between BVDV-1 and BVDV-2 VN titre against BVDV-1 strains BVDV-2 strains Serum against BVDV-1 strains 800->12,800 100->3,200 BVDV-2 strains 50->400 3,200->51,200 Pellerin et al.(1994) Virology 203:260-268

  28. Intra-species PI carriers Inter species Vaccine related? Artificial breeding programs Blood Persistence in acutely infected animals Pathogenesis - infection

  29. Pathogenesis

  30. Sub-clinical Mild fever, leukopenia, decreased milk production Mild BVD - mild erosive lesions, ulcerative stomatitis, diarrhoea, respiratory Severe disease - lesions mimic MD, thrombocytopenia, haemorrhagic syndrome, hyphemia Pathogenesis - disease in imm.competent, non-pregnant animals

  31. All syndromes described above Embryonic death Abortions Birth defects Persistently infected calves Pathogenesis - pregnant animals

  32. Healthy, normal “poor-doers” Mucosal disease Pathogenesis - PI animals

  33. Guess which one is persistently infected? Calves of the same age. From Lee et al. CVJ 38:29

  34. consequences of having a PI animal • Loneragan et al. JAVMA, Feb 15, 2005 • PI animals more likely to be ill, require treatment or die • Incontact animals more likely to be sick, require treatment • Dieguez et al. Res Vet Sc, Aug 2009 • Correlation BVD status and respiratory disorders, mortality

  35. NCP->CP (p80) Infection with antigenically related CP virus (mutation, herd-mate, vaccination?) Low morbidity high mortality High fever, depression, anorexia, diarrhoea Ulcerative mucosal lesions Death 2 days -> 3 weeks Mucosal disease

  36. Mucosal Disease (by mutation) MD

  37. Mucosal Disease (by infection or injection) MD

  38. No Mucosal Disease if CP virus antigenically different No MD Immune response

  39. Virus isolation Small numbers ($31.50) Herd screening - microtitre ($10 -2->10, $6 >10) Antigen capture ELISA Herd screening Serology VN ($14) ELISA ($5/animal) PCR genotyping ($62) pooled samples ($30) Diagnostic procedures

  40. PCR (BVDV-1 vs BVDV-2) Immunohistochemistry or IFA Abortions ($45) PI animals (approx. $6/animal) BVDV-1a BVDV-2 BVDV-1b Diagnostic procedures

  41. Immunohistochemistry - PI vs acute From Brad Njaa et al. 2000. J. Vet. Diag. Invest. 12:393-399. Persistently infected calf: Antigen in hair follicle epithelium Acutely infected calf: Antigen in superficial layer of epidermis (foci)

  42. Diagnostic Parameters (acute infection) infection incubation period antibody 5-7 days clinical disease virus infect. virus detectable in serum infect. virus detectable in WBC Virus det. by PCR antigens in biopsy

  43. Fetus Often no infectious virus Submit liver, kidney, spleen, thymus for IH or IFA Fetal antibody if late term Diagnostic parameters (abortion)

  44. Large amounts of virus in blood, serum and secretions (103-107 TCID50/ml) Maternal antibody interferes with isolation <3 months - submit blood >3 months - serum Repeat isolation in 3 months Immunohistochemistry - follicle epithelium Diagnostic parameters (PI)

  45. Herd screening

  46. Test and remove PI animals Test all new born calves for 9 months For 9-12 months segregate age groups Quarantine replacements Vaccination with MLV BVDV BVD infections may persist for some time after removal of PI animals (Collins et al. 2009) Management of BVD

  47. Inactivated or attenuated Most (all) contain CP BVDV Vaccines

  48. http://www.cattlenetwork.com/content.asp?contentid=119624

  49. Sheep Wild ruminants Natural infections (caribou: 40-100%) Transfer (llamas, alpacas) Interspecies transfer