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Dengue fever

Dengue fever

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Dengue fever

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  1. Dengue fever Shuchismita Dutta March 24, 2011

  2. Resource • HHMI holiday lectures 2010 (http://www.hhmi.org/biointeractive/lectures/index.html) • Dr. Eva Harris • Professor of Infectious Disease @ UC Berkley • founder and president of Sustainable Sciences Institute • Dr. Joe DeRisi • Hughes Investigator, Biochemistry and Biophysics, UCSF

  3. What is Dengue Fever? • Caused by Dengue virus • Symptoms: • fever, headache, skin rash, muscle and joint pain • Severe form: hemorrhagic fever, fluid leakage, bleeding in the GI tract (could be fatal) • Prevalent in tropical countries (urban disease) • Spread by mosquito (Aedes aegypti)

  4. History of Dengue • Earliest record as water poison in Chinese encyclopedia (265 to 420 A.D.) • 17th century reports of disease in Panama, West Indies and Southeast Asia. • Global pandemic following world war II • In Americas: • 1950’s to 1970’s disease was rare due to mosquito control • Once mosquito control was stopped the disease re-emerged

  5. Increased incidence of Dengue • Uncontrolled urbanization • Poor water, sewer an waste management • Lack of effective mosquito management • Global travel (for work and vacation) • Lack of public health infrastructure in many countries (Demographic and Societal changes)

  6. Dr. Harris talks about Dengue, Nicaragua and her work • Chapters 3-16 in lecture 1 in DVD • Chapters 21-32 in lecture 1 in DVD • Discussion

  7. Dengue Virus • Member of Flaviviridea • Same family as West Nile virus, Japanese encephalitis virus, tick-borne encephalitis virus • Uses mosquito (Aedes aegypti) as a vector for infecting humans • 4 strains – DENV1, 2, 3, 4

  8. Anatomy of the Dengue Virus • Enveloped virus • Has a lipid bilayer coat • Genetic material is ssRNA virus (+ive sense) • RNA is covered by nucleocapsid Nature Structural Biology10, 907 - 912 (2003)

  9. Dengue Infection • Dr. Harris talks about the Dengue infection and antibody dependent enhacement (ADE) of disease • Chapters 4-9 in lecture 3 of DVD

  10. Dengue Virus: RNA and Proteins • 11kb positive sense RNA • Structural proteins • C • prM • E • Non-structural proteins • NS1 • NS2A/B • NS3 • NS4A/B • NS5 Complete Dengue virus structure (PDB ID 1k4r) Kuhn et al., 2002 180 copies of E protein

  11. Dengue Virus Polyprotein UNP ID: P29990 (POLG_DEN26)

  12. Dengue E-prM Proteins prM – precursor Membrane protein Envelope protein Domain III Fusion peptide Domain I E-prM heterodimer (PDB ID 3c6e) Li et al., 2008 Domain I

  13. Capsid Protein Membrane Viral RNA NMR structure of Capsid protein PDB ID 1r6r Ma et al., 2004

  14. NS3 Protein: Protease - Helicase NS2B Protease cofactor Protease N-terminal domain Helicase active site Motifs I-VI Helicase C-terminal domain Helicase and Protease (PDB ID 2vbc) Luo et al., 2008

  15. NS5 Protein: N-Terminal Domain Methyltransferase CAP that is added to the RNA in the methyltransferase site S-adenosyl homocystine (reaction product) Methyltransferase for capping the RNA (PDB ID 2P1D) Egloff et al., 2002

  16. NS5 Protein: RdRp (Residues 270-900) Fingers domain Thumb domain Zn Active site Zn Mg NLS Palm domain Catalytic domain on RNA dependent RNA polymerase (PDB ID 2J7U) Yap et al., 2007

  17. Dr. DeRisi describes the Dengue Virus life cycle • Animation in DVD

  18. Dengue Detection • Virus specific antibody based diagnostics • Chapter 13 (Lecture 2 on DVD) • RNA hybridization • Chapter 30 (Lecture 2 on DVD)

  19. Dengue: Prevention & Treatment • Mosquito control • Community based most effective • Vaccine • Live attenuated virus (currently acts like an antiviral) • Effective vaccine in development • Antivirals • Potential target RNA dependent RNA polymerase

  20. References Structure primary citations: • Ma L, Jones CT, Groesch TD, Kuhn RJ, Post CB (2004). Proc Natl Acad Sci U S A. 9;101(10):3414-9. (PDB ID 1r6r) • Kuhn RJ, Zhang W, Rossmann MG, Pletnev SV, Corver J, Lenches E, Jones CT, Mukhopadhyay S, Chipman PR, Strauss EG, Baker TS, Strauss JH. (2002) Cell. Mar 8;108(5):717-25. (PDB ID 1k4r) • Yap TL, Xu T, Chen YL, Malet H, Egloff MP, Canard B, Vasudevan SG, Lescar J. (2007) J Virol. May;81(9):4753-65. Epub 2007 Feb 14. (PDB ID 2j7u) • Egloff MP, Benarroch D, Selisko B, Romette JL, Canard B. (2002) EMBO J. Jun 3;21(11):2757-68. (PDB ID 2p1d) • Li L, Lok SM, Yu IM, Zhang Y, Kuhn RJ, Chen J, Rossmann MG. (2008) Science. Mar 28;319(5871):1830-4. (PDB ID 3c6e) Reviews: • Mukhopadhyay S, Kuhn RJ, Rossmann MG. (2005) Nat Rev Microbiol. Jan;3(1):13-22. • Perera R, Kuhn RJ. (2008) Curr Opin Microbiol. Aug;11(4):369-77. Epub 2008 Jul 31. • Gubler DJ. (1998) Clin Microbiol Rev. Jul;11(3):480-96.