1. 3 Togaviruses
Flaviviruses

2. Togaviruses and Flaviviruses (C63, p637)
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)
Exceptions:
a. Rubella virus
b. Hepatitis C virus
Table Togaviruses and Flaviviruses
Virus Group
Human Pathogens
Togaviruses
Alphavirus
Arboviruses
Rubivirus
Rubella virus
Pestivirus
None
Arterivirus
Flaviviruses
Hepaciviridae
Hepatitis C virus

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

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.
l  Besides viral receptor, virus may attach to Fc receptor (macrophages and
monocytes) via Ab to result in an increase of virus infection.
l Antibody is produced to block infection. However, non-neutralizing Ab
may have antibody dependent enhancement (ADE) effect to enhance
virus replication by hundred folds.

7. BOX 63-2. 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 Syndrome
Encephalitis
Hepatitis
Hemorrhage
Shock
Dengue +
Yellow fever
St. Louis encephalitis
West Nile encephalitis
Venezuelan encephalitis
Western equine encephalitis
Eastern equine encephalitis
Japanese encephalitis

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

9. Page 642 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 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. BOX 63-3. 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. a. togavirus encephalitides (mostly are not in Taiwan) b. flaviviruses
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.
The West Nile virus infection in US is similar to the Japanese encephalitis virus in Taiw

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 as 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)
Taiwan has all 4 serotypes, so the chance of
Developing DHF/DSS is increasing.

16. b3. Epidemiology
There are 100 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.

17. Please practice the case study of dengue infection in p. 648.

18. ex: Yellow fever virus induces yellow fever.
The disease is characterized by severe systemic disease, with generation 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).
The mortality rate is as high as 50%, but life long immunity.

19. 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.  

20. 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.

21. --Cell-mediated immunity helps to resolve infection.
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.

22. l Congenital rubella syndromes
3-13
l Congenital rubella syndromes
BOX 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

23. Table 63-3. Estimated Morbidity Associated with the 1964-1965 U. S
Table Estimated Morbidity Associated with the U.S. Rubella Epidemic
Clinical Events
Number Affected
Rubella cases
12,500,000
Arthritis-arthralgia
159,375
Encephalitis
2,084
Deaths
  Excess neonatal deaths
2,100
  Other deaths 60
  Total deaths
2160
Excess fetal wastage
6250
Congenital rubella syndrome
  Deaf children
8055
  Deaf/blind children
3580
  Mentally retarded children
1790
  Other congenital rubella syndrome symptoms
6575
  Total congenital rubella syndrome
20,000
Therapeutic abortions
5000

24. * * * * BOX 63-4. 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. * * * *

25. l 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 rebella infection in p. 648.

26. 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.
What features of these cases pointed to the diagnosis of
dengue virus infection?
Of what significance was the trip to Malaysia?
What was the source of infection in the father and son?
What were the significance of and the pathogenic basis for the
petechiae and ecchymoses in the child?

27. The diagnosis of dengue virus infection is indicated by the disease signs of high fever, severe headache, and joint and back pain. The patient's trip to Malaysia would have increased his risk of exposure to Aedes mosquitoes carrying the virus.
The Aedes mosquito is endemic in Malaysia and is a carrier of dengue virus, which is prevalent in Malaysia.
The virus was transmitted independently by different mosquitoes to the father and son.
Petechiae and ecchymoses are indicators of hemorrhagic disease.

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.
What features of this case pointed to the diagnosis of rubella infection?
Why is it significant that the symptoms started after a trip outside the
United States?
What precaution could the man have taken to prevent this infection?
How was this infection transmitted?
Who was at risk for a serious outcome of this infection?
If this disease is normally mild in children, why is their immunization so
important?

29. The diagnosis of rubella infection is suggested by the arthralgia and especially the mild rash. These immune-mediated responses occur after the virus replication and viremic spread, which induces interferon, causing the influenza-like syndrome.
Exposure to rubella in the United States is unlikely because of the U.S.'s effective vaccine program.
If the man had been immunized with the MMR (measles, mumps, rubella) vaccine and received his booster immunization at 15 years of age, he should have been protected against rubella disease.
Rubella is the only togavirus that is transmitted by aerosols as a respiratory virus.
All unimmunized individuals are at risk for this infection. However, the most serious outcomes occur to the fetus of women who are infected prior to the 20th week of pregnancy. Rubella causes severe congenital defects.
Immunization of the populace (especially children) for rubella prevents congenital defects in babies.