1. 1 Togaviruses and Flaviviruses (C62, p609)

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

3. 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) Virus GroupHuman Pathogens Togaviruses AlphavirusArboviruses RubivirusRubella virus ArterivirusNone FlavivirusesArboviruses PestivirusNone Table 62-1. Togaviruses and Flaviviruses Not arbovirus

4. 4 The nomenclature of arboviruses are mostly based on endemic areas and symptoms induced by viruses, including fever, encephalitis and hemorrhagic fever (Table 2)

5. 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. 6 4. Pathogenesis and immunity Transmission: viremic verterbrate hosts  blood-feeding arthropod (female mosquito, persistently infected)  infect another host and cause damage (death) of target cells 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.

7. 7 BOX 62-2. Disease Mechanisms of Togaviruses and Flaviviruses Viruses are cytolytic, except for rubella. Viruses establish systemic infection and viremia. Viruses are good inducers of interferon, which can account for the flulike symptoms of infection. Viruses, except rubella and hepatitis C, are arboviruses. Flaviviruses can infect cells of the monocyte-macrophage lineage. Non-neutralizing antibody can enhance flavivirus infection via Fc receptors on the macrophage. Flulike SyndromeEncephalitisHepatitisHemorrhageShock Dengue+ +++ Yellow fever+ +++ St. Louis encephalitis++ West Nile encephalitis++ Venezuelan encephalitis++ Western equine encephalitis++ Eastern equine encephalitis++ Japanese encephalitis++

8. 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. 9 Page 614 Fig. 4

10. 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)

11. 11 BOX 62-3. Epidemiology of Togavirus and Flavivirus Infection Disease/Viral Factors Enveloped virus must stay wet and can be inactivated by drying, soap, and detergents. Virus can infect mammals, birds, reptiles, and insects. Asymptomatic or nonspecific (flulike fever or chills), encephalitis, hemorrhagic fever, or arthritis. Transmission Specific arthropods characteristic of each virus (zoonosis: arbovirus). Who Is at Risk? People who enter ecologic niche of arthropod: arboviruses. Geography/Season Endemic regions for each arbovirus are determined by habitat of mosquito or other vector. Aedes mosquito, which carries dengue and yellow fever, is found in urban areas and in pools of water. Culex mosquito, which carries St. Louis encephalitis and West Nile encephalitis viruses, is found in forest and urban areas. Disease is more common in summer. Modes of Control Mosquito breeding sites and mosquitoes should be eliminated. Live attenuated vaccines are available for yellow fever virus and Japanese encephalitis virus (killed).

12. 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. 13 ex. Japanese encephalitis virus a1. Transmission : pig, horse, cow, bird  mosquito ( 三斑家蚊 ) → humans 。

14. 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. 15 ex: dengue fever (caused by 4 serotypes of dengue virus) 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. 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. 18 Please practice the case study of dengue infection in p. 620.

19. 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. 20 8. Diagnosis: Virus is identified by isolation, cytopathological studies, immunofluorescence, and RT-PCR. 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. 21 9. Rubella virus (There is only one serotype ) 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. 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. 23 Congenital rubella syndromes BOX 62-5. Prominent Clinical Findings in Congenital Rubella Syndrome Cataracts and other ocular defects Heart defects Deafness Intrauterine growth retardation Failure to thrive Mortality within the first year Microcephaly Mental retardation

24. 24 Clinical EventsNumber Affected Rubella cases12,500,000 Arthritis-arthralgia159,375 Encephalitis2,084 Deaths Excess neonatal deaths2,100 Other deaths60 Total deaths2160 Excess fetal wastage6250 Congenital rubella syndrome Deaf children8055 Deaf/blind children3580 Mentally retarded children1790 Other congenital rubella syndrome symptoms 6575 Total congenital rubella syndrome 20,000 Therapeutic abortions5000 Table 62-3. Estimated Morbidity Associated with the 1964-1965 U.S. Rubella Epidemic

25. 25 BOX 62-4. Epidemiology of Rubella Virus Disease/Viral Factors Rubella infects only humans. Virus causes asymptomatic disease. There is one serotype. Transmission Respiratory route. Who Is at Risk? Children: Mild exanthematous disease. Adults: More severe disease with arthritis or arthralgia. Neonates younger than 20 weeks: Congenital defects. Modes of Control Live attenuated vaccine is administered as part of measles, mumps, and rubella (MMR) vaccine. * * * * *

26. 26 Before 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.

27. 27 CASE STUDY AND QUESTIONS A 27-year-old businessman experienced a high fever, serious retroorbital headache, and severe joint and back pain 5 days after he and his family returned from a trip to Malaysia. The symptoms lasted for 4 days, and then a rash appeared on his palms and soles that lasted for 2 days. At the same time the man's 5-year-old son experienced mild flulike symptoms and then collapsed after 2 to 5 days. The boy's hands were cold and clammy, his face was flushed, and his body was warm. There were petechiae on his forehead and ecchymoses elsewhere. He bruised very easily. He was breathing rapidly and had a weak rapid pulse. He then rapidly recovered after 24 hours. 1. What features of these cases pointed to the diagnosis of dengue virus infection? 2. Of what significance was the trip to Malaysia? 3. What was the source of infection in the father and son? 4. What were the significance of and the pathogenic basis for the petechiae and ecchymoses in the child?

28. 28 Two weeks after returning from a trip to Mexico, a 25-year-old man had arthralgia (joint aches) and a mild rash that started on his face and spread to his body. He recalled that he had felt as if he had the flu a few days before the onset of the rash. The rash disappeared in 4 days. 1. What features of this case pointed to the diagnosis of rubella infection? 2. Why is it significant that the symptoms started after a trip outside the United States? 3. What precaution could the man have taken to prevent this infection? 4. How was this infection transmitted? 5. Who was at risk for a serious outcome of this infection? 6. If this disease is normally mild in children, why is their immunization so important?