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RNA Polymerase = enzyme that makes mRNA from the DNA gene template

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Presentation on theme: "RNA Polymerase = enzyme that makes mRNA from the DNA gene template"— Presentation transcript:

1 RNA Polymerase = enzyme that makes mRNA from the DNA gene template
The DNA -> RNA -> Protein Pathway RNA Polymerase = enzyme that makes mRNA from the DNA gene template

2 Plus-strand RNA Viruses
Plus-strand RNA viruses have genomes comprised of RNA. They have no DNA in their replication cycles. In most cases, the replication cycle takes place in the cytoplasm of the cells. No involvement of the transcription machinery in the nucleus; so, the plus-strand RNA viruses produce their own enzymes for RNA transcription and replication, which recognize RNA as the template. The plus-strand RNA viruses do use the host cell’s translation machinery to generate viral proteins. Many plus-strand RNA viruses produce numerous viral proteins from a single “gene.”

3 Types of Plus-Strand RNA Viruses with single-stranded, non-segmented plus-strand genomes
Genome Polarity Polymerase in Virions? RNA by itself infectious? Types of mRNAs Types of protein products Example virus family I + (mRNA) No Yes One Long polyprotein; subsequently cleaved Picornaviruses (ex. Rhinovirus) Flaviviruses (ex. West Nile Virus) II Multiple One for each mRNA Coronaviruses Class

4 Picornavirus Diseases
ENTEROVIRUSES (stable in GI tract) Poliomyelitis Hepatitis A Virus Coxsackieviruses Enteroviruses Types 68-72 Echoviruses RHINOVIRUSES (not stable in GI tract) Common Cold Numerous subtypes

5 Fecal-Oral Transmission

6 Enterovirus Pathogenesis: Target Tissues

7 Poliovirus Pathogenesis
Only a fraction of patients develop paralytic disease Asymptomatic infection – 90% Abortive/minor illness – 5% Non-paralytic progression to the CNS – 1%-2% Paralytic poliovirus – 0.1%-2% 3-4 days after minor illness Virus infects motor neurons in anterior horn of spinal cord and the motor cortex

8 Poliovirus Infection: Progression to CNS Disease

9 Protection by Antibodies
Secretory antibodies can prevent primary infection Serum antibodies prevent viremic spread to target tissues

10 Poliovirus Vaccination
Salk Vaccine Killed Virus (formalin inactivated) IPV Sabin Vaccine Live, attenuated viruses OPV Attenuated strains can revert to virulent forms Vaccinees shed the attenuated viruses in feces Plusses Minuses

11 WHO Eradication of Poliovirus
Eradication campaign started in 1988 Current target date for eradication: Beyond 2009

12 Is Eradication Possible?
Oral Poliovirus Vaccine Preferred for Third World Vaccination Cheaper, No Sterile Needles Required Campaign of usage has drastically reduced wild poliovirus transmission Major issue is REVERSION of OPV strains to virulent forms Laboratory Stocks Poliovirus present in many laboratories around the World Poliovirus contaminants in stocks of other viruses, i.e. Coxsackievirus, Rhinovirus Bioterrorism cDNA copies of poliovirus genome exist in many laboratories; transfection into tissue culture cells results in virus production The poliovirus genome has been generated on a gene synthesizer (Plus-strand RNA viral genomes alone are infectious!)

13 Picornavirus Diseases
ENTEROVIRUSES (stable in GI tract) Poliomyelitis Hepatitis A Virus Coxsackieviruses Enteroviruses Types 68-72 Echoviruses RHINOVIRUSES (not stable in GI tract) Common Cold Numerous subtypes

14 Human Rhinovirus Structure
5’-NTR Open Reading Frame Encoding Polyprotein AAAAAAAA ~630 nts VPg ~7200 bases

15 Human Rhinovirus Structure
Virus exterior = protein shell Icosahedral shape Cross-section Viral RNA genome inside Protein capsid layer outside

16 Rhinovirus Life Cycle

17 Rhinovirus Binding to Receptor and Antibodies
ICAM-1 RECEPTOR BOUND TO RHINOVIRUS ANTIBODIES BOUND TO RHINOVIRUS

18 ICAM-1 Receptor Binds to Canyon on Rhinovirus Surface

19 Rhinovirus Life Cycle

20 Rhinovirus Polyprotein Processing: Method for Generation of Individual Viral Proteins

21 Rhinovirus Life Cycle

22 Rhinovirus Pathogenesis
Entry of virus into upper respiratory tract Hands and fomites Inhalation of droplets that contain virus Unable to replicate in the GI tract (not stable to acid) Receptor is ICAM-1 (Intercellular Adhesion Molecule 1) Preferentially replicates at 33oC Over 100 serotypes Reason for repeat infections throughout lifetime Antigenic sites change, but receptor-binding site is protected

23 Rhinovirus Pathogenesis

24 Targets for Rhinovirus Therapy

25 New Rhinovirus Therapies
62 million cases of Rhinovirus infection in U.S. each year Cause more than 50% of respiratory tract infections Traditional vaccine approaches as with poliovirus not possible (too many serotypes), so antiviral therapies must exploit unique properties of the virus Soluble ICAM-1: Blocks virus binding to its receptor AG7088: 3C protease inhibitor (being formulated for intranasal delivery) Pleconaril: Binds a pocket in the capsid; interferes with attachment and uncoating Promising early clinical studies – reduction in disease length Not approved due to possible drug-drug interactions Reformulations being developed

26 West Nile Virus

27 Types of Plus-Strand RNA Viruses with single-stranded, non-segmented plus-strand genomes
Genome Polarity Polymerase in Virions? RNA by itself infectious? Types of mRNAs Types of protein products Example virus family I + (mRNA) No Yes One Long polyprotein; subsequently cleaved Picornaviruses (ex. Rhinovirus) Flaviviruses (ex. West Nile Virus) II Multiple One for each mRNA Coronaviruses Class

28 Flavivirus Gene Structure
(West Nile Virus = member of Flavivirus family) Figure 1. Genomic structure of flaviviruses. The flavivirus genome is 11,000 to 12,000 nucleotides long. Both the 5'- and 3'- ends contain noncoding (NC) regions. The genome encodes 10 proteins, 3 of which are structural proteins (C, M, and E), and 7 of which are nonstructural proteins (NS1, NS2a, NS2b, NS3, NS4a, NS4b, and NS5). The M protein is synthesized as a precursor (prM) protein. The prM protein is processed to pr + M protein late in the virus maturation by a convertase enzyme (furin).

29 West Nile Virus Genetic Structure and Protein Expression
virol/flavi1.jpg

30 West Nile Virus Structure

31 West Nile Virus Replication Cycle
*The WNV receptor in vertebrate cells is V3 integrin, which is highly conserved in vertebrates Figure 2 The WNV replication cycle. A. Attachment and entry of the virion. B. Uncoating and translation of the virion RNA. C. Proteolytic processing of the polyprotein. D. Synthesis of the minus-strand RNA from the virion RNA. E. Synthesis of nascent genome RNA from the minus-strand RNA. F. Transport of structural proteins to cytoplasmic vesicle membranes. G. Encapsidation of nascent genome RNA and budding of nascent virions. H. Movement of nascent virions to the cell surface. I. Release of nascent virions. SHA, slowly sedimenting hemagglutinin, a subviral particle that is also sometimes released.

32 Coronaviruses Another virus group with members responsible for the “common cold” Coronavirus member in the news = SARS Virus

33 Types of Plus-Strand RNA Viruses with single-stranded, non-segmented plus-strand genomes
Genome Polarity Polymerase in Virions? RNA by itself infectious? Types of mRNAs Types of protein products Example virus family I + (mRNA) No Yes One Long polyprotein; subsequently cleaved Picornaviruses (ex. Rhinovirus) Flaviviruses (ex. West Nile Virus) II Multiple One for each mRNA Coronaviruses Class

34 Coronaviruses

35 Coronaviruses

36 Coronaviruses

37 Coronavirus Receptor = ACE-2
ACE-2 = angiotensin-converting enzyme 2 Expressed in heart, lung, kidney, GI tract

38 SARS Virus Budding

39 Targets for SARS Therapy


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