DENGUE VIRAL

Titiek Djannatun
Department of Microbiology Faculty of Medicine
YARSI University

ARBOVIRUS YANG SEBABKAN PENYAKIT DEMAM DAN HEMORRHAGIC

VIRUS

PENYAKIT

DISTRIBUSI

VEKTOR

HEW.
RESERVOAR

YELLOW FEVER (ALPHAVIRUS)

FEVER, HEPATITIS

AFRIKA, AMERIKA
TENGAH & SELATAN

Aedes spp

Monyet hutan

DENGUE (4 SEROTIPE)
(FLAVIVIRUS)

FEVER, RASH (HEM

SYOK SYNDROME)

INDIA, ASIA TENGGARA,

PASIFIK, AMERIKA
SELATAN, KARIBIA

NYAMUK

Monyet hutan

KYASANUR FOREST (FLAVIVIRUS)

HEMORRHAGIC
FEVER

INDIA

TICK

MONYET, RODENTS

ROSS RIVER (BUNYAVIRUS)

FEVER, ARTHRALGIA,
ARTHRITIS

AUSTRALIA, KEP
PASIFIK

NYAMUK

UNGGAS

RIFT VALLEY FEVER

(BUNYAVIRUS)

FEVER, KADANG
HEMORRHAGIC

AFRIKA

NYAMUK

SAPI, ONTA, DOMBA

SANDFLY FEVER (BUNYAVIRUS)

FEVER

ASIA, AMERIKA
SELATAN,
MEDITERANIAN

TICKSANDFL
YS

GERBILS

CONGO CRIMERIAN
HEMORRHAGIC FEVER
(BUNYAVIRUS)

FEVER,
HEMORRHAGIC

ASIA, AFRIKA

TICK

RODENTS

COLORADO TICK FEVER

(REOVIRUS)

FEVER, MYALGIA

USA (ROCKY
MOUNTAINS)

TICK

RODENTS

LA CROSSE (BUNYAVIRUS)

FEVER

USA

NYAMUK

RODENTS, DLL

Dengue Fever
What is it?
Mode of transmission
Symptoms and treatment
Prevention

What is Dengue Fever?

Dengue fever, also know as breakbone fever, is an acute

communicable disease caused by virus.

Caused by Dengue viruses (categorizes into types
1,2,3,4)
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 but in Hongkong by

Aedes albopictus) as vector

Aedes albopictus as a potential vector (in lab) this
mosquito lifes outside home

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:
1950s to 1970s disease was rare due to
mosquito control
Once mosquito control was stopped the disease
re-emerged

Dengue
Dengue is the biggest arbovirus problem in the world today with

over 2 million cases per year. Dengue is found in SE Asia, Africa

and the Caribbean and S America.
Flavivirus, 4 serotypes, transmitted by Aedes mosquitoes which

reside in water-filled containers.

Human infections arise from a human-mosquitoe-human cycle
Classically, dengue presents with a high fever, lymphadenopathy,

myalgia, bone and joint pains, headache, and a maculopapular rash.

Severe cases may present with haemorrhagic fever and shock with a

mortality of 5-10%. (Dengue haemorrhagic fever or Dengue shock

syndrome.)

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)

Distribution of Dengue

Mode of Transmission
A healthy person gets the disease when he is

bitten by an infected mosquito. The virus enters

his blood from the mosquitos saliva.
An infected person could transmit the virus to

mosquitoes if he is bitten by a mosquito anytime

from the onset to the subsidence of the fever (a
period of about 6 to 7 days). The disease is then
spread by mosquitoes.
Dengue fever is not spread by contact

with infected persons.

10

Transmission

Infected
mosquito

Healthy person
Incubation Period: 3 to 14 days
Most commonly 4 to 7 days

Infected
person

11

Types

Classical
dengue

Dengue
haemorrhagic
fever

Dengue
Dengue haemorrhagic fever and shock syndrome appear most

often in patients previously infected by a different serotype of

dengue, thus suggesting an immunopathological mechanism.
Diagnosis is made by serology.
No specific antiviral therapy is available.
Prevention of dengue in endemic areas depends on mosquito
eradication. The population should remove all containers from
their premises which may serve as vessels for egg deposition.
A live attenuated vaccine is being tried in Thailand with
encouraging results.

Vectors

Aedes aegyti

Aedes albopictus

The life cycle of a vector mosquito is divided

into the 4 stages: egg, larva, pupa and adult

14

Symptoms of
Classical Dengue (1)
Fever: continuous for 3 to 5 days
Severe headache
Painful limbs, joint pain, muscle

pain, back pain, pain behind

eyeballs

15

Symptoms of
Classical Dengue (2)
Rash appears on the 3rd to 4th day after onset.
Nausea, vomiting.
Slight gum bleeding and nasal bleeding.
Extreme fatigue and depression may follow

recovery.
In very rare cases, the condition may worsen
into dengue haemorrhagic fever, leading to
haemorrhage, shock or even death.

Dengue Virus
Member of Flaviviridea
Same family as West Nile virus, Japanese encephalitis virus, tickborne encephalitis virus
Uses mosquito (Aedes aegypti) as a vector for infecting

humans
Genus Flavivirus
4 strains DENV1, 2, 3, 4
Rod shape, 45-60nm in diameter
Haemagglutinable
Thermolabile
Sensitive to inactivated by diethyl ether-2, Na-dioxicolate, acid
pH, detergent
Stable at 700C
Replication in sitoplasma and passage in RES

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 Biology 10, 907 - 912 (2003)

Dengue Virus: RNA and Proteins

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

PATHOGENESIS FLAVIVIRUS

PATHOGENESIS FLAVIVIRUS

MANIFESTASI KLINIS
DEMAM DENGUE
Masa inkubasi 1-2 minggu, menggigil, demam sampai 400C
sakit kepala, sendi dan otot
Demam menurun setelah 7 hari makulapapula exanthema
betis
DEMAM BERDARAH DENGUE
Perdarahan pada kulit dan organ
Ptechie, hidung berdarah (juga pada lubang lain), Feses
berdarah, Hematuria
DENGUE SYOK SYNDROME
Perdarahan pada organ
Masa darah pada otak CNS
10-40% MENINGGAL

Typical infectious cycle

1. Attachment
2. Penetration

3. Uncoating
4. Transcription and/or
translation
5. Replication
6. Assembly

7. Release

RNA virus
replication

Replication Strategy of ss(+)RNA Viruses

Steps in Replication
1. Translation of virion RNA as mRNA (early products = RNADependent RNA Pol)

2. Synthesis of (-)sense RNA on (+)sense template by RDRP (=

formation of replicative complex, RC)
3. Synthesis of (+)sense RNA, mRNA and (-)sense RNA
4. Translation of (+)sense and mRNA, synthesis of structural
protein

5. Assembly of structural protein and (+)sense RNA and

maturation of virions

MORPHOGENESIS FLAVIVIRUS

Patogenesis Dengue
Virus menginfeksi monosit akibatnya CD4+ dan CD8+
(Limfosit T) Teraktivasi
CD8+ (limfosit T) serang monosit dan berinteraksi
dengan CD4+ Cytokine teraktivasi (IL-1, IL-2,
TNF-) Permeabilitas kapiler meningkat
sebabkan hemorrhagic dan syok syndrome (lebih
hebat lagi pada infeksi yang kedua)

MANIFESTASI KLINIS
SYOK Hipersensitivitas
Hemokosentrasi
Beberapa hari setelah infeksi kedua dibentuk
kompleks virus dan Ab Ab tidak menambah
netralisasi virus Komplemen teraktivasi
memacu infeksi virus ke sel-sel mononuklear
meningkat + pelepasan sitokin, mediator
vasoaktif+ pro koagulan Pembekuan intra
vaskuler Tersebar DIC SYNDROME
DEMAM BERDARAH

Diagnosis
Serology - usually used to make a diagnosis of arbovirus

infections.
Culture - a number of cell lines may be used, including

mosquito cell lines. However, it is rarely carried out since

many of the pathogens are group 3 or 4 pathogens.
Direct detection tests - e.g detection of antigen and nucleic

acids are available but again there are safety issues.

Isolation and Serology

Isolation:
Intra cerebral inoculation at baby mouse
Mammalia cell culture (LLC-MK2)
Intra thoracal inoculation at mosquito

Hemagglutinin inhibition test

Serology
CFT
Netralisasi test
Mc ELISA
IgG ELISA

Dengue rapid test

PCR

Prevention
Surveillance - of disease and vector populations
Control of vector - pesticides, elimination of breeding

grounds
Personal protection - screening of houses, bed nets, insect

repellants
Vaccination - available for a number of arboviral infections

e.g. Yellow fever, Japanese encephalitis, Russian tickborne encephalitis

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

PENCEGAHAN DAN PENGOBATAN DENGUE

Tidak ada obat/vaksin untuk pencegahan dengue
Pencegahan Jangan sampai terinfeksi
Istirahat dan minum banyak
Pada derajat IV Cairan tubuh harus dimonitor
Obat mengatasi gejala (symptomatic)
Fever Acetaminophen
Aspirin dan ibuprofen Hindari ANTIKOAGULAN
Live Attenuated Vaccine CLINICAL TRIAL
Sedang dikembangkan vaksin secara bioteknologi dan genetic
engineering
Pencegahan HINDARI GIGITAN Aedes aegypti (PAGI,
MENJELANG MALAM)

36

If you suspect that you have

dengue fever, the most
important thing to do is to

see a doctor.

37

Lets remove stagnant water

and eliminate mosquitoes