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STOP BVD

STOP BVD. Ernst Peterhans Institute of Veterinary Virology University of Bern, Switzerland. How BVDV escapes and subverts immune defenses. 1. Acknowlegments All scientists and farmers who have contributed to our knowledge At home: Matthias Schweizer and crew. 3.

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STOP BVD

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  1. STOP BVD

  2. Ernst Peterhans Institute ofVeterinaryVirology University ofBern, Switzerland How BVDV escapesandsubverts immune defenses 1

  3. Acknowlegments All scientistsandfarmerswhohave contributed to our knowledge At home: Matthias Schweizer and crew 3

  4. The virusandthehost: A matter ofconflictingaims The virus: topersist in thepopulation The host: topropagate (humans ??) Forthevirus: twooptions: „hitandrun“ or: „infectandpersist

  5. Examples: Hit andrun: rabies, mumps Infectandpersist: herpes, lenti

  6. Rabies: the fate of the host video

  7. Rabies: the fate of the virus in a closed host population

  8. The twooptionshavelimitations: • „hit and run“ works if: • probability of transmission to next host host is high • parameters:structure, density and dynamics of host population ? • extent and duration of viral shedding ? • dose required for infection? Most oftheseinfectionscanbecontrolledbyvaccination Vaccinesagainstmostoftheseinfectionsareproblematic „infect and persist“ works if - cost for infected individual islowto moderate - virusmust be able to outsmartitshost‘simmune system - forlife ! 6 1

  9. BVD: subversionstartswithstrategy „hit and run“ : transient infectionand „infect and persist“ : persistent infection Vaccines ??

  10. Interaction of BVDV withitsnaturalhost: basics

  11. Interaction of BVDV withitsnaturalhost: basics immunotolerance

  12. immunotolerance • definedbyadaptiveimmunity: T and B cell • highlyspecificforinfecting viral strain • consequencefor viral evolution ? • immunotoleranceseemstobecomplete – • but some PI animalsshowantibodiesto BVDV clinically, PI animalsmaybe „normal“, orshow reducedgrowthandfrequentinfections  persistent infectionmaybe „perfect“ – ornot

  13. persistent infectionmaybe „perfect“ – orlessthanperfect Bynecessity(*), mostofusaremoreinterested in „less-than –perfect“ aspectsof viral infectionsthan in viral perfection (*)  „less-than-perfection“

  14. The type of host cell is important: Monocytesand DCs Chris Howard/Bryan Charleston andcolleagues: Antigen-presentingcellsfrom PI calvesare „normal“ Monocytes (MO) and DCs susceptibletoinfection, but only MOs killedbycp BVDV. Resistance of DCs not due to IFN MOs, but not DCs infectedwithncp BVDV, showdecreased memoryorallogeneicTcellstimulation Detected a „PDC-like –PDC unlike“ cell type thatproduces IFN-I in responsetoncp BVDV (a myeloidcell type) 14

  15. The type of host cell is important: Monocytesand DCs LesyaPinchukandcolleagues: monocytes cpandncp BVDV disruptearlyantigenuptake in monocytes, thismightberelatedtospecificimmunotolerance in PI Early upregulationof TLR3 in ncp BVDV infectedmonocytes Upregulation (24hpi) of TLR7 in cpandncpinfectedmonocytes Downregulationof TNF-α, IL-1β, IL-6 Downregulationofthereceptorofactivated C kinase, pyridoxal kinase, Brutons tyrosinekinase in cp BVDV vsncpinfected monocytes 14

  16. The type of host cell is important: Mφshowfunctionalchanges in responsetoinfection withBVDV: in vitro plus factor „X“ 14

  17. Roth, Bolin andcolleagues: lymphocytesand PMNs reporteddefectivefunctionsof PMNs andlymphocytes isolatedfrom PI animals Neill, Ridpathandcolleagues: Infectionhasprofoundimpact on transcriptionof multiple genes  effectsmaybecomeapparent „whenthecellisasked to do something“: priming General conclusionfromthesestudies: BVD virusescause a widearrayoffunctional changesthatmayexplainaspectsofdisease …back tothisatthe end !

  18. Interaction of BVDV withitsnaturalhost: basics onlyncpcan do !

  19. Thoushalt not kill is smart: ncp BVDV Smart viruses make use of Jiv ! - cp BVDV maybe viewed as loss-of-function mutants in bovine turbinatecells: ncp biotype cp biotype overexpression of bcl-2 triggers apoptosis no apoptosis, no IFN induces interferon-I … 13

  20. Interferons: the basics: Type I interferons: α, β, δ, έ, τ, ώ: shared receptor antiviral, immunomodulatory , cytostatic Type II interferon: γ: immunomodulatory Type III interferons: λ1, λ2, λ2 (IL29, IL28A, IL28B) Induction Action Randall and Goodbourn, J. Gen. Virol. 89, 1, 2008

  21. The type of host cell is important: Mφ show a functionalchanges in responsetoinfection withBVDV: in vitro plus factor „X“ factor „X“: primes culturedcellsforapoptosis in responseto LPS 14

  22. Mucosal disease: why are the lesions where they are? A contributionoffactor „X“? Cp BVDV ncp BVDV but, occasionally, also between the claws and on (thin) skin 15

  23. Viral infection Innate Immunity Pathogen structure not recognized Pathogen structure (PAMP) recognized Interferon, IL-1, etc. Innate antiviral immune reactions No immune reaction Antibodies cTx Adaptive immunity Activation of innate immunity is essential for triggering adaptive immunity

  24. 0 0.1 1 10 100 [ng/ml] IFN treatment before ncp strain SD-1 (moi = 0.01) 0 0.1 1 10 100 [ng/ml] IFN treatment after ncp strain SD-1 (moi = 0.01) 0.2 mm IFN continued: BVDV is sensitive to IFN-I: but is not eliminated once infection is established 25

  25. 890 0 1 10 100 Suwa 0.2 mm Cells remain infected after 10 passages inpresence of interferon Doesviruspersisting in itshostcellssimplyinhibit the action of interferon - like many other viruses do ? 26

  26. Mock Mock Degree of apoptosis VSV replication (titer) rbo IFNα VSV ncp BVDV ncp BVDV The simple approach: testif a virus „newcomer“ isinhibited in BVDV-infectedcells after IFN-treatment 27

  27. Bovine turbinatecellsinfectedwithncp BVDV still establish antiviral state: the „newcomer“ VSV isinhibited 28

  28. IFN-b non-self 3 IFN-b VSV IFN-b IFN-b EMCV 1 ds RNA /ssRNA P P Jak-Statsignaltransduction IRF-3 IRF-3 P OAS,RNAse L P 2 IFN-b BVDV PKR self Mx P Npro BVDV ATF-2 p50 c-JUN P p65 NF-kB ISGs IFN-bgene Cell I: IFN-a/b induction Cell II: IFN-a/b activity BVDV andIFN-a/β: discriminationbetween „self“ and „non-self“

  29. NS 4A NS4B C p7 NS5A NS5B Npro Npro 5´-UTR 3´-UTR cellular proteases (signal peptidase; signal peptide peptidase) viral proteases (NS2, NS3) Erns Erns E1 E2 structural proteins non-structural proteins NS2 NS3 Of the Flaviviridae only the pestiviruses encodethe N-terminal protease Npro and the RNAseErns.

  30. NS 4A NS4B C p7 NS5A NS5B Npro Npro 5´-UTR 3´-UTR cellular proteases (signal peptidase; signal peptide peptidase) viral proteases (NS2, NS3) Erns Erns E1 E2 structural proteins non-structural proteins NS2 NS3 Of the Flaviviridae only the pestiviruses encodethe N-terminal protease Npro and the RNAse Erns. Activatesproteasomaldegradation ofinterferonregulatoryfactor 3 (IRF-3)  targetsintracellulardsRNA

  31. NS 4A NS4B C p7 NS5A NS5B Npro Npro 5´-UTR 3´-UTR Erns Erns E1 E2 NS2 NS3 Of the Flaviviridae only the pestiviruses encodethe N-terminal protease Npro and the RNAse Erns. Present on viral particle, lackstypicaltransmem-braneanchor secretedfrominfectedcells, hasRNAseactivitywithpreferenceforssRNA

  32. Erns Iqbal et al., 2004 Baculovirus-producedErnstargetsextracellulardsRNA (poly-IC) Magkouras et al., 2008 Free Ernsispresent in bloodof PI animals in concentrations similartothoseeffective in preventing IFN induction in vitro AuthenticErnsprevents IFN inductionbypoly-IC Mätzener et al., 2008 AuthenticErnsprevents IFN inductionby BVDV dsandssRNA RNAseactivityiscrucialforthiseffect

  33. IFN-b IFN-b IFN-b IFN-b P P IFN-b IRF-3 dsRNA IRF-3 P P IFN-b IFN-b Npro P p50 ATF-2 p65 c-JUN P NF-kB IFN-bgene BVDV-infected cell X X

  34. Erns Erns BVDV Erns IFN-b Erns IFN-b Erns TLR IFN-b IFN-b Erns P P P P IFN-b IRF-3 IRF-3 dsRNA IFN-b IRF-3 IRF-3 P P IFN-b P P IFN-b IFN-b IFN-b Npro P P p50 p50 ATF-2 ATF-2 p65 p65 c-JUN c-JUN P P NF-kB NF-kB IFN-bgene IFN-bgene BVDV-infected cell Non-infected cell X X

  35. Erns • Ernsis a novel type ofvirus-encodeddecoyreceptor: • minimizesdanger (andbenefit !) ofactivating • innate immune response • Viral PAMP becomespartof „self“ • efficient: enzymaticallyinactivates viral PAMP • thatisconstantlyproduced in PI animals • possible prime targetcell: • natural IFN-producingcell, • pDC ?

  36. plasmacytoid dendritic cells other cells recognition of NA in cytoplasm ssRNA cpG DNA dsRNA 5‘PPP RNA dsRNA

  37. plasmacytoid dendritic cells other cells recognition of NA in cytoplasm ssRNA cpG DNA dsRNA 5‘PPP RNA dsRNA

  38. …andnow: back tothe „imperfection“ of BVDV Thisviruscausesdisease, in transientlyas well as well as in some PI animals: General conclusionfromthesestudies: BVD virusescause a widearrayoffunctional changesthatmayexplainaspectsofdisease And also cytokines, especially IFN-1 cancausedisease:

  39. IFN during fetal developmentand post partum: Cpandncp BVDV, transient and persistent infections Bryan Charleston andcolleagues: fetus: ncpearly: - cpearly: + postnatal tr.Incp + Thomas Hansen andcolleagues: fetus: ncpearly: -/+ ncplate: + postnatal PI ncp + Yamaneandcolleagues: postnatal tr. I ncp + postnatal PI + Metzler andcolleagues postnatal tr.I + 14

  40. IFN during fetal developmentand post partum: Cpandncp BVDV, transient and persistent infections Conclusion: a generalagreement on theactivationof theinnate immune responsetocpandncp BVDV late in intrauterine developmentand post partum (transient infection) more divergent interpretation in persistent infection in (early) fetusand PI animal WHY ? 14

  41. No final explanations – but herearesomemoderatelyeducatedguesses: (1) PI animalsarechimeric with respect to BVDV: how does the innate immune system of the non-BVDV part of PI animals handle BVDV ? 32

  42. No final explanations – but herearesomemoderatelyeducatedguesses: Ontogenyof „natural IFN producingcells“ ? different virulenceof BVDV strains ? viral load dsandssRNA (PAMP) levels different efficiencyof viral „attenuationmechanisms“ 32

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