Togaviruses and Flaviviruses (C62, p609)

1. Togaviruses and Flaviviruses (C62, p609)

2. 1. Structure (+ssRNA, icosahedral capsid and envelope)(Fig. 1)

3. 2.Most members are arthropod-borne viruses (arboviruses, 節肢動物媒介病毒) Infect vertebrate hosts and induce viremia persistent productive infection of blood-feeding arthropod (broad host range including vertebrates and invertebrates; zoonoses) Table 62-1. Togaviruses and Flaviviruses Not arbovirus

4. Disease Vector Host Distribution Disease Alphaviruses Sindbis* Aedes and other mosquitoes Birds Africa, Australia, India Subclinical Semliki Forest* Aedes and other mosquitoes Birds East and West Africa Subclinical Venezuelan equine encephalitis Aedes, Culex Rodents, horses North, South, and Central America Mild systemic; severe encephalitis Eastern equine encephalitis Aedes, Culiseta Birds North and South America, Caribbean Mild systemic; encephalitis Western equine encephalitis Culex, Culiseta Birds North and South America Mild systemic; encephalitis Chikungunya Aedes Humans, monkeys Africa, Asia Fever, arthralgia, arthritis Flaviviruses Dengue* Aedes Humans, monkeys Worldwide, especially tropics Mild systemic; break-bone fever, dengue hemorrhagic fever, and dengue shock syndrome Yellow fever* Aedes Humans, monkeys Africa, South America Hepatitis, hemorrhagic fever Japanese encephalitis Culex Pigs, birds Asia Encephalitis West Nile encephalitis Culex Birds Africa, Europe, central Asia, North America Fever, encephalitis, hepatitis T2 St. Louis encephalitis Culex Birds North America Encephalitis Russian spring-summer encephalitis lxodes and Dermacentor ticks Birds Russia Encephalitis Powassan encephalitis lxodes ticks Small mammals North America Encephalitis The nomenclature of arboviruses are mostly based on endemic areas and symptoms induced by viruses, including fever, encephalitis and hemorrhagic fever (Table 2)

5. 3.  Replication --  Viral genome includes early (nonstructural) and late (structural) proteins. Genome arrangement is different between togaviruses and flaviviruses (Fig. 3). -- Viral replication process includes the entry by receptor-mediated endocytosis, uncoating, protein (a single polyprotein ) synthesis, viral genome synthesis, assembly, and virus release by budding from plasma membrane or internal membrane (flaviviruses).

6. 4.  Pathogenesis and immunity l  Transmission: viremic verterbrate hosts  blood-feeding arthropod (female mosquito, persistently infected)  infect another host and cause damage (death) of target cells l  Disease development: viremia mild systemic disease might be due to interferon production after infection (fever, chills, headaches, backaches, etc., influenza-like symptoms) encephalitis, hepatitis, and arthrogentic (hemorrhage) disease.

8. The nature of alphavirus and flavivirus diseases is determined primarily by • the specific tropisms of the individual virus type • the concentration of virus, and • individual host response to the infection.

9. Page 614 Fig. 4

10. 5.  Epidemiology (1) Arboviruses are able to infect both vertebrates and invertebrates, initiate viremia in vertebrates, and initiate a persistent productive infection of the salivary gland of invertebrate. Humans are usually “dead-end” hosts. (2) Death of infected no-human vertebrates, such as birds, occurs before human outbreak. (3) In winter, virus persist in arthropod eggs or migrate with birds. (4) Sylvatic (jungle) cycle (monkeys  arthropods  humans) urban cycle (humans  arthropods  humans)

12. 7.  Clinical symptoms: a. togavirus encephalitides (mostly are not in Taiwan) b. flaviviruses ex: Outbreak of West Nile virus has occurred in US since 1995 West Nile Encephalitis: During August, a 70-year-old man from a swampy area of Louisiana develops fever, headache, muscle weakness, nausea, and vomiting. He has difficulty answering questions. He progresses into a coma. Magnetic resonance imaging results show no specific localization of lesions (unlike in herpes simplex virus encephalitis). His disease progresses to respiratory failure and death. His 25-year-old niece, living next door, complains of sudden onset of fever (39°C [102.2°F]), headache, and myalgias, with nausea and vomiting lasting 4 days. Please also see P. 616 for a clinical case of West Nile virus infection The West Nile virus infection in US is similar to the Japanese encephalitis virus infection in Taiwan.

13. ex. Japanese encephalitis virus a1. Transmission : pig, horse, cow, bird  mosquito (三斑家蚊) → humans。

14. a2. Pathogenesis: attack the CNS and induce mortality 。 (There are 50,000 infection cases/year. Among these, 1/200 cases develop disease.) a3. Infection provides life long immunity. a4. Killed virus is used for vaccine.

15. ex: dengue fever (caused by 4 serotypes of dengue virus) l Pathogenesis: 埃及或白線斑蚊→humans →cause fever (DF), headache, rash, and back and bone pain for 6 to 7 days (break-bone fever) dengue hemorrhagic fever (DHF) dengue shock syndrome (DSS)

16. Besides viral receptor, virus may attach to Fc receptor (macrophages and monocytes) via Ab to result in an increase of virus infection. • Antibody is produced to block infection. However, non-neutralizing Ab from the previous infection with a different serotype may have antibody dependent enhancement (ADE) effect to enhance virus replication by hundred folds. • Taiwan has all 4 serotypes, so the chance of developing DHF/DSS is increasing.

17. b3. Epidemiology • There are up to 50 million DF and 300,000 DHF/DSS cases per year. • DHF and DSS are due to antibody dependent enhancement (ADE) • induced by to infection with different serotypes of virus.

18. Please practice the case study of dengue infection in p. 620.

19. ex: Yellow fever virus induces yellow fever. --The disease is characterized by severe systemic disease, with degeneration of the liver, kidney, and heart, as well as hemorrhage. --Liver involvement causes the jaundice from which the disease gets its name, but massive gastrointestinal hemorrhages (black vomit) may occur. --The mortality rate is as high as 50%. --Infection and vaccination provide life long immunity.

20. 8. Diagnosis: l Virus is identified by isolation, cytopathological studies, immunofluorescence, and RT-PCR. l Serology is confirmed by the presence of virus specific IgM or a 4-fold increase in antibody titer. 10. No treatment exists for arbovirus diseases other than supportive care. 11. Vector control is used to prevent virus spread. 12. Vaccines are available for some viruses, such as JEV and yellow fever virus.

21. 9.  Rubella virus (There is only one serotype )   • l It cause respiratory infection, • classic childhood exanthems • (German measles; Fig. 8), and • severe congenital defects. • Pathogenesis and immunity (Fig. 6, 7) upper respiratory tract infection • local lymph nodes (lymphoadenopathy) •  viremia tissues  rash.

22. Immune response • --Antibody production correlates with rash appearance, so immune complex • causes rash. • --Cell-mediated immunity helps to resolve infection. • --Serum antibody provides life-long protection and prevents virus spread to • fetus in pregnant women. • Clinical syndromes • --Benign symptoms develop in children, • but more severe problems (bone and • joint pain, thrombocytopenia or • encephalopathy) occur in adults • (due to hypersensitivity or • cell-mediated immunopathology). • Rubella: A 6-year-old girl from Romania develops • a faint rash on her face and is accompanied by • mild fever and lymphadenopathy. Over the next 3 • days the rash progresses to other parts of the body. • She has no history of rubella immunization.

23. lCongenital rubella syndromes

24. Table 62-3. Estimated Morbidity Associated with the 1964-1965 U.S. Rubella Epidemic

25. * * * * *

26. lBefore vaccination, congenital infection causes 1 % neonatal • abnormality. (Vaccination reduces congenital infection to • <1 to 0.1 per 100,000 pregnancies) • Lab. Diagnosis --It is difficult to isolate virus. --Virus is detected by RT-PCR. --Serology Please practice the case study of rubella infection in p. 648.