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Samira Mubareka , MD Dept. Microbiology and Division of Infectious Diseases

Samira Mubareka , MD Dept. Microbiology and Division of Infectious Diseases Sunnybrook HSC and Research Institute samira.mubareka@sunnybrook.ca. Mandell Field’s Virology Clinical Virology (Hayden) Red Book TWIV: This Week In Virology (iTunes) http://www.twiv.tv/

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Samira Mubareka , MD Dept. Microbiology and Division of Infectious Diseases

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  1. Samira Mubareka, MD Dept. Microbiology and Division of Infectious Diseases Sunnybrook HSC and Research Institute samira.mubareka@sunnybrook.ca

  2. Mandell • Field’s Virology • Clinical Virology (Hayden) • Red Book • TWIV: This Week In Virology (iTunes) • http://www.twiv.tv/ • Persiflager’s Infectious Diseases Puscast (iTunes)

  3. Retroviruses HIV I/II HTLV I/II DNA RNA Arthropod- borne/zoonotic Arenaviruses Alphaviruses Bunyaviruses Flaviviruses Rhabdoviruses P2P Acute Adenovirus Parvovirus Poxvirus HHV6/7 Latency HSV, VZV, CMV Polyomaviruses Oncogenic EBV, HHV8 HBV Papillomaviruses GI Picornaviruses Caliciviruses HCV Resp Orthomyxoviruses Paramyxoviruses Filoviruses

  4. Advances in Virology Reverse genetics

  5. Advances in Virology • New platforms: • Mass spec • High-throughput screening • Confocal and immunofluorescence microscopy • Flow cytommetry • Tissue culture, VLPs • Sequence databases, bioinformatics • RNAi • Genomics and novel animal models

  6. Nature Reviews Microbiology 5, 453-463 (June 2007)

  7. Fields’ (Skip Virgin): • Sequential: more readily correlated with disease • Stochastic events and bottlenecks • Viral determinants vs. host selection • Integrated effects of host genetic variations • Immunogenetics • Other considerations: • Tissue tropism • Viral inoculum (effect on incubation period & outcome; eg. ebola) • Route of transmission • Socioeconomic factors/poverty

  8. Entry via: • contact /MM (incl sexual) • Parenteral • oral (organ infectivity=109 pfu/g) • Target cells: monos, macrophages, DCs • GP binds host cell receptor (DC-SIGN?)  hepatocytes, splenocytes, fibroblasts, adrenal cortical cells • Viremia: 106-108 pfu/ml; direct EM+ RNA polymerase

  9. Extensive liver, spleen, adrenal, gonadal necrosis without infiltration: • Hepatcellular necrosis with ghostlike cells • Intracytoplasmic inclusion bodies • Tissue damage correlates with viral Ag and NA • Elevated LFTs; coagulation dysfunctionhemorrhage (GI bleeding) • Adrenal involvementhypotension

  10. Lymphoid depletion in lymphatic tissues with minimal infiltrate; lymphopenia (T cells and NKs) • TNF-related apoptosis-inducing ligand (TRAIL) • Fas death receptor pathways • Pro-apoptotic NO • Proinflammatory cytokines • IL-6/8/10/12, IP-10, MCP-1, RANTES, TNF-α, reactive oxygen and nitrogen spp.increased vascular permeability

  11. IFN-antagonism: VP35 (block IRF-3) & VP24 • GP, secreted (putative): vascular injury & hemorrhagic diathesis • Endovascular lesions not consistently seen in humans; intact vascular endothelium in animal models, though increased permeability noted • Persistence: viral RNA identified in semen up to 100d post-infection

  12. Subtyping: 16 HA 9 NA A/Toronto/R8557/2009(H1N1) Virus type Strain # Geographic origin Year Virus subtype Horimoto, T. Nature Microbiology Reviews 2005;3:351-600

  13. Nasal mucosa Paranasal sinuses Bronchus Bronchiole Alveolus K. Shinya, Nature, 2006;440:435-436

  14. NA Krug, RM, Lamb, RAOrthomyxoviridae: The Viruses and Their Replication 2001 Fields Virology. 4th edition, editors: Knipe DM, Howley PM,. Philadelphia: Lippincott Williams & Wilkins.

  15. Hale, et al. J Gen Virol 2008;89:2359-2376

  16. 1918 HA (Ian Wilson,Scripps) Connenello & Palese. Cell Host & Microbe, 2007;2(4):207-209

  17. www.clinical-virology.org/gallery/images/em/rabies2.jpg

  18. Pathogenesis • Bites: local replication in striated muscle • Other routes: aerosol, parenteral, Tx, oral, vertical • Viral GP binds host cell receptors in NMJ: • post-synaptic nicotinic ACH receptor; hence fox is susceptible & possums are resistant • CD56 • Neurotrophin receptor p75 • Retrograde motor neuron transport (50-100mm/d) via viral P protein-dynein interactiontransynaptic transfer of nucleocapsid (viral G protein)

  19. Pathogenesis Diffuse centrifugal spread (NOT viremia) Viral shedding in lacrimal & salivary glands Immune response: none until symptom onset Neutralizing antibody CD4+ T cells and B cells central; viral N protein epitopes

  20. Furious rabies (brainstem, CN, limbic) Paralytic rabies (medulla, spinal cord)

  21. PV capsid interacts with host cell receptor CD155

  22. 100 TCID50infection Resistance to acid Fecal shedding=6 weeks Replication in tonsils/ Peyer’s patches (1-3d) Deep cervical/mesenteric nodes with minor viremia RES (LN/BM/liver/speen) With major viremia CNS invasion (across BBB & retrograde) Cutter’s vaccine incident & provocation poliomyelitis Virology. 2006 Jan 5;344(1):9-16

  23. tonsil Peyer’s appendix rectum PV1 capsid proteins in L ant horn of spinal cord 33h post- gastoc Infection of CD155tg mouse Immunofluorescence analysis of CD155 Virus Res. 2005 Aug;111(2):175-93

  24. Neurovirulence • Sabin strains • 5’ UTR mutations destabilize secondary structure • VP 1,3,4 (PV1) • VP 1 (PV2) • VP 1,3 (PV3) PV incorporated into endosomes at NMJ after viremia and muscle seeding or GIvagal nerve Virus Res. 2005 Aug;111(2):175-93

  25. Innate immunity (type 1 IFNs) • Humoral immunity (not sterilizing) • Persistent enteroviral infections in Ig-deficient states • Neutralizing epitope in capsid protein • VP1 and 2C protease contain T cell epitopes

  26. Viral E2 binds putative host cell receptor CD81 Primary replication in liver within 2d of infectionviremia vRNA isolated from PBMCs, LN, spleen, brain, adrenals, BM, pancreas, thyroid Quasispecies result of stochastic events Nature Reviews Microbiology 5, 453-463 (June 2007)

  27. K/O in HCV-permissive cells K/O in HCV-permissive cells NS5 & E2 interfere in JAK/STAT pathway http://www.nature.com/onc/journal/v25/n51/fig_tab/1209941f4.html

  28. T cells key: hosts who have robust CD4+ response clear virus Nature Reviews Immunology 5, 215-229 (March 2005)

  29. Elevated AST temporally relates to CD8+ cytotoxic activity and fall in VL

  30. Inflammation & Fibrosis • Periportal lymphocytic infiltration, hepatocellular necrosis • Mediated by NK and T cells as well as hepatic stellate cells (fibrogenic, synthesis of collagen) • Steatosis • Core protein & genotype 3 are key viral determinants • Block assembly & release of VLDL, interfere with PPARα • Mitochondrial injury

  31. Hepatocellular carcinoma • HCV does not integrate into the host genome • HCC due to ongoing fibrosis, oxidative stress, etc… • Core protein, S3, NS5A/B may be oncogenic by modulating cell proliferation

  32. Lymphoproliferative disorders • Mixed cryoglobulinemia (polyclonal IgG & IgM, types II and III respectively) due to clonal B cell expansion • Small vessel vasculitis • Peripheral neuropathy • MPGN • NHL • *Porphyria cutanea tarda, lichen planus • Sjogren’s syndrome • Chronic polyarthritis

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