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1、Picornaviruses (微小核糖核酸病毒),General introduction Physical and structure properties Viral replication Virus-host interaction,General introduction,脊髓灰质炎病毒及疫苗,手足口病,EV70-急性出血性眼结膜炎、脑膜炎、瘫痪型疾病、多发性神经根炎。,患者眼部常可并发细菌感染。儿童病例23天痊愈，成人12周内完全恢复。,Foot and Mouth Disease,Incubation period: 2-12 days Lesion in teats and
2、hoofs Fever and vesicles Feet, mouth, nares muzzle, teats Progress to erosions Abortion Death in young animals Recover in two weeks unless secondary infections arise,FMD distribution (2003),The picornaviruses, More than 200 viruses prevalent world-wide. Cause many serious diseases of animals and man
3、. Foot and mouth virus first animal virus described (1898).First identified RNA-dependent RNA polymerase is that of mengovirus. Poliovirus is an important model:- first virus purified and crystallized.- first inactivated vaccine used (Salk 1950s).- first picornavirus to be sequenced.- first mRNA sho
4、wn to lack of 5 cap structure.- first picornavirus structure to be solved.,PICORNAVIRUS PROPERTIES,Capsids are small unenveloped 25 -30 nm icosahedra.Resistant to pH 3 to 9 (except for Rhinoviruses).Plus sense single stranded RNA genomes (7400 bases).Genome is monopartite.RNA 5 end has a covalently
5、attached VPg (22-24 aa) and 3 end is polyadenylated.The 5 end contains a highly structured (740 nt) untranslated region that contains IRES and several AUGs.The naked RNA is sufficient for infection.The RNA is translated into a polyprotein that is cleaved intoenzymatic and structural proteins. The vi
6、rus replicates in the cytoplasm.,Virus transmission and entry,Transmission of enterovirus in human body,Replicates in Nasopharnyx,Binds Enterocytes Receptor,Evades,Acidic PH,Endocytosed , replication in Peyers patches,Minor Viraemia, Replication in organs,Major Viraemia + Trophism + Virulence,Skelet
7、al Muscle Neuromuscular Endplate,Ascends along Motor Nerves,Anterior Motor Neuron horncells To CNS*,Specifc for polio,HAV的致病性,粪口途径传播,小肠淋巴结中大量增殖,入血并形成病毒血症,肝脏为最终靶器官（病毒直接损伤或免疫病理作用）,通过胆汁随粪便排出体外,Capsid is an icosahedron consisting of 60 identical asymmetric protomers arranged as 12 pentamers. Each protom
8、er is composed of a single copy of each of the four capsid proteins, VP1, VP2, VP3 and VP4. (VP0 in parechoviruses replaces VP4+VP2). VP4 is located on the inner surface of the protein shell formed by VP1, VP2 and VP3. All three proteins contain a central bbarrel jelly roll. The jelly roll is a wedg
9、e-shaped structure that consists of two antiparallel b-sheets.,Picornavirus Capsid Structure,楔形物,Picornaviruss Bind to Many Different Host Receptors,Scr-short consensus repeat LDL-low density lipoprotein T/S/P threonine/serine/proline,IG Like - Members of the immunoglobulin family of receptors found
10、 on cells of the immune system.,CVB1-6,PV,CVA13，18，21,Ence。V,CVB1, 3, 5 EV3, 6,7 etc.,HAV,Rhino. V,EV1, 8,Parechovirus 1,Yamayoshi, S. et al. Nat. Med. 15, 798801 (2009). Nishimura, Y. et al. Nat. Med. 15, 794797 (2009).,Receptors identified for hand, foot and mouth virus,CNS papers do not means it-
11、is-true!,Icam-1 Receptor,A canyon is formed at the junction of VP1 and VP3 in the capsids of rhinoviruses and some enteroviruses like poliovirus. The canyons are the sites of interaction with cell surface receptors. As the picornavirus binds to Icam-1, the host receptor penetrates into the viral can
12、yon and this causes a change in conformation of the capsid to permit virus entry. Some antiviral drugs (WIN compounds) can irreversibly replace the lipid that lines the tunnel and inhibit uncoating and in some cases attachment of the virus.,Nonenveloped poliovirus enters cells by forming a pore in t
13、he membrane of the cell.During interactions of poliovirus with its receptor major conformational rearrangements occur in the virus particle. The particles lose VP4 and the hydrophobic N-terminus of VP1 is displaced to the virion surface。 N-termini of VP1 forms a pore in the cell mebrane through whic
14、h the RNA is released into the cytosol.Some evidence suggests that virus particles may undergo endocytosis in some cell types.,Entry of Poliovirus into Cells,Translation and replication,Poliovirus Genome organization,Poliovirus genome contains a single ORF (7209-8450b). It has VPg at its 5 end and a
15、 poly(A) tail at its 3 end.,Processing occurs in 3 steps. The first is to cleave the P1 capsid protein precursor, which is catalyzed by 2Apro. The second step is to process the noncapsid and the capsid precursors catalyzed by 3Cpro and 3CDpro. The third step is the processing of VP0 into VP4 and VP2
16、.,Polyproteins are proteolytic processed during translation,Protein functions,VP1-4: capsid coat proteins 2A: protease 2B: membrane permeability, involved at an early step of viral RNA synthesis. 2C: RNA helicase, ATPase, may direct replication complexes to cell membranes.3A: RNA replication 3B: Genome-linked protein (VPg, primer) 3C or 3CD: protease 3D: RNA-dependent RNA polymerase 2BC: critical to viral replication 3AB: anchors VPg in membranes for the priming step of RNA synthesis.,
