s3 l16 flaviviridae

8/8/2019 S3 L16 flaviviridae

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S3 L16: Flaviviridae by Dra. Madrid DDD eee ccc eee mmm bbb eee rrr 111 ,,, 222 000 111 000

Genus Flaviviruso once classified in the Togaviridae as group B arboviruses

Genus Pestivirus o Includes animal pathogens (bovine viral diarrhea and hog choleraviruses) that are of considerable economic importance, but

contains no known human pathogens.

Genus Hepacivirus

All flaviviruses that cause disease in humans are arthropod-borneviruses (arboviruses ).

Virus Primary vector Vertebratereservoir Geographicdistribution

Dengue 1, 2,

3, 4 Aedes aegypti Human,

monkeysTropics

Japaneseencephalitis Culex Birds Asia

St. Louisencephalitis Culex Birds, pigs Americas

West Nile Culex Birds Africa, tropical Asia,Mediterranean

Yellow Fever Aedes aegypti Humans,monkeysTropical Africa andthe Americas

Omskhemorrhagicfever

Dermacentor Rodents Central Russia

Tick-borneencephalitis Ixodes

Rodents,birds,dometiscatedanimals

Russia, EasternEurope,Scandinavia

Louping Ill Ixodes Sheep, birds British Isles

Powassan Ixodes SmallmammalsCanada, US,Russia

Kyansanur ForestDisease

Haemaphysalis Rodents Southwest India

Murray Valleyencephalitis/Kunjin Rocio

Culex Birds Australia, NewGuinea

Virus DiseaseDengue 1, 2, 3, 4 Fever, rash, arthralgia, myalgiaJapanese encephalitis EncephalitisSt. Louis encephalitis EncephalitisWest Nile Fever, rash, arthralgia, myalgiaYellow Fever Fever, hemorrhage, jaundiceOmsk hemorrhagic fever Fever, hemorrhageTick-borne encephalitis EncephalitisLouping Ill EncephalitisPowassan EncephalitisKyansanur Forest Disease Fever, hemorrhage, encephalitisMurray Valley encephalitis/ KunjinRocio

Encephalitis

PATHOGENIC FLAVIVIRUSES

3 groups according to symptoms they cause:Meningoencephalitides

o SLE, JE, MVE and TBEFever-arthralgia-rash syndrome

o DEN, WN, KUN Hemorrhagic fever syndrome

o Omsk hemorrhagic fever, Kyasanur Forest dse viruYF, DEN

FLAVIVIRUS STRUCTURE

Virion: spherical, 40-50 nm in diameter Nucleocapsid contains capsid protein (C)Single positive strand RNA (40S, 10.9 kilobases)

o Capped at the 5 end but unlike alphaviruses, hasno poly segment at the 3 end

Envelope: lipid bilayer o a. envelope protein (E) [51,000-59,000 daltons]o b. small nonglycosylated protein (M) [8,500 daltons]o Only E, which is glycosylated in most flaviviruses, is cledemonstrable on the virion surface

Virions mature at intracytoplasmic membranesMost members are transmitted by bloodsucking arthropodsInactivated by: acid pH, heat, labile solvents, detergents, bleach, phen

70% alcohol, formaldehydeMost possess hemagglutinating activity

All are antigenetically related

STRUCTURAL PROTEIN FUNCTIONS

C highly basic component of the nucleocapsidprM precursor of M proteinM protein: membrane-associated and serve a matr

function, linking capsid and envelopeE major envelope protein; virion assembly, receptor bindingmembrane fusion

NONSTRUCTURAL PROTEIN FUNCTIONS

NS1: membrane soluble hemagglutininNS3: protease/ polymeraseNS5: polymerasens2a : works in tandem with NS3 as a protease

MULTIPLICATION

Genomic RNA is capped(not polyadenylated) andserve as mRNA for allproteins

Structural proteins areencoded at the 5 end of the genome: nonstructuralproteins (e.g. RNA dependent RNApolymerase) are encodedin the 3 two-thirds

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Complementary (antisense) RNA, made from the genomic RNA, serves as atemplate for progeny genomic RNA

Replication occurs in the cytoplasm (20-30 hours)Entire virus genome is translated as a single polyprotein which is thencleaved into the mature proteinso Structural proteins: encoded at the 5 end

o Nonstructural proteins (eg. NS-1 and RNA-dependent RNApolymerase): encoded at the 3 two thirds

Complementary negative strand RNA is synthesized by NS protein andthen is used as a template for genomic progeny RNA synthesis Assembly occurs characteristically into cytoplasmic vacuoles (inassociation with Golgi or smooth membranes)Release occurs when cell lyses

Pathogenesis and Clinical Manifestations

Flaviviruses vary widely in their pathogenic potential andmechanisms for producing human diseaseit is useful to consider them in three major categories:

o those associated primarily with the encephalitis syndrome(prototype: St. Louis encephalitis),o those associated with fever-arthralgia-rash (prototype: dengue

fever), or o With hemorrhagic fever (prototype: yellow fever).

Human infection initiated bydeposition of virus throughthe skin via the saliva of aninfected arthropod replicates locally & inregional lymph nodes viremiaMost human infections withSt. Louis enceph (SLE) &Jap enceph (JE) viruses,there is either no apparentdisease or a nonspecificfebrile illness withheadache.infection resolves, and lasting immunity is producedCNS invasion may develop: aseptic meningitis or encephalitisIn the great majority of flavivirus infections, virus is cleared by theimmune system.

o however, persistence in neurological tissue has been notedwith tick-borne encephalitis viruses, and recent reports of recurrent encephalitic bouts in children have been associatedwith JE virus recovery from peripheral blood mononuclear cells

Host Defenses

Lasting protection is generally restricted to the same flavivirus, is associated with neutralizing antibodies.

ARTHROPOD-BORNE VIRUSES

Arthropod-borne viruses (Arboviruses) WHO definition:

Viruses maintained in nature principally through biologicaltransmission between susceptible vertebrate hosts byhaematophagus arthropods.

ARBOVIRUSES BELONG TO THREE FAMILIES

Togaviruses o EEE, WEE, and VEE

Bunyaviruses o Sandfly Fever, Rift Valley Fever, Crimean-Congo

Haemorrhagic Fever Flaviviruses

o Yellow Fever, dengue, Japanese encephalitis

TRANSMISSION CYCLES

Man-arthropod-mano E.g. Dengue, urban yellow fever o reservoir may be in either man or arthropod vector o in the latter, transovarial transmission may take place

Animal-arthropod vector-mano eg. Japanese encephalitis, jungle yellow fever o reservoir is an animalo Virus is maintained in nature in a transmission cycle

involving the arthropod vector and animal. Man becominfected incidentally.

Both cycles may be seen with some arboviruses such as yellowfever

ARTHROPOD VECTORS Mosquitoeso JE, Den, Yellow Fever, SLE

Ticks o various tick-borne encephalitides, etc

Examples of Arthropod Vectors

Culex mosquito Aedes aegypti Assorted ticks

ANIMAL RESERVOIRS

In many cases, the actual reservoir is not known. The following animals implicated as reservoirs

Birds Japanese encephalitis, St Louis encephalitis

Pigs Japanese encephalitisMonkeys Yellow Fever Rodents Russian Spring-Summer encephalitis


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DISEASE CAUSED

Fever and rash o this is usually a non-specific illness resembling a number

of other viral illnesses such as influenza, rubella, andenterovirus infections. The patients may go on to developencephalitis or haemorrhagic fever.

Encephalitis o SLE, JE

Haemorrhagic fever o

yellow fever, dengueDIAGNOSIS

Serology o usually used to make a diagnosis of arbovirus infections.

Culture o a number of cell lines may be used, including mosquitocell lines. However, it is rarely carried out since many of thepathogens are group 3 or 4 pathogens.

Direct detection tests o e.g detection of antigen and nucleic acids are availablebut again there are safety issues.

PREVENTION

Surveillance o of disease and vector populations

Control of vector o pesticides, elimination of breeding grounds

Personal protection o screening of houses, bed nets, insect repellants

Vaccination o available for a number of arboviral infectionso e.g. Yellow fever, Japanese encephalitis, Russian tick-

borne encephalitis---------------------------------------------------------------------------------------------------------

JAPANESE ENCEPHALITIS

First discovered and originally restricted to Japan. Now large scaleepidemics occur in China, India and other parts of Asia.Flavivirus, transmitted by Culex mosquitoes.The virus is maintained in nature in a transmission cycle involvingmosquitoes, birds and pigs.Most human infections are subclinical: the inapparent to clinicalcases is 300:1In clinical cases, a life-threatening encephalitis occursThe disease is usually diagnosed by serology. No specific therapy isavailable.Since Culex has a flight range of 20 km, all local measures will fail.

An effective vaccine is available.Infections during the 1st and 2nd trimesters of pregnancy havereportedly led to fetal death

JE Virus: VIROLOGYJapanese encephalitis (JE) serocomplex

o 10 viruseso 6 human pathogens (JE, West Nile, Kunjin, Usutu, St.

Louis encephalitis, Murray Valley encephalitis viruses)o Most are amplified bird-mosquito-bird

5 genotypes in Asia (most isolates in genotype 1)

JE Virus: HISTORY

1871: Summer encephalitis epidemic in Japan

1924: Agent from human brain tissue isolated in rabbits1934: Isolate of this virus produced experimental encephalitismonkeys1938: First isolate fromCulex tritaeniorhynchus 1930s: First mouse brain-derived vaccines developed1954: Refined mouse brain vaccine developed

WHY IS JE A PROBLEM?

JE is the leading cause of viral encephalitis in Asia, now t

poliomyelitis has nearly been eradicated.More than 3 billion people live in areas where JE is transmitted.50,000 cases of JE are reported to WHO each year.10,000 to 15,000 deaths are reported each year.

CASES ARE UNDER-REPORTED

Cases are under-reported due too Lack of good surveillance systems.o Lack of diagnostics.

Actual number of cases is probably more than 175,000 per year.

CLINICAL SPECTRUM OF JE DISEASE

DEATH AND DISABILITY FROM JE

Up to 30% of all patients with JE die.For those that survive the illness, 30% to75% cases are left wdisability.Disability is both physical and cognitive.

AGE GROUPS AFFECTED BY JE

Children 1 to 15 years of age are mainly affected in endemic areaBut people of any age can be infected. Adult infection most ofoccurs in areas where the disease is newly introduce

Different patterns of age distribution of cases

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TWO PATTERNS OF TRANSMSSION OF JE:

JE may be spread:

1. Seasonal, called anepidemic pattern (e.g.,southern China)

2. Year-round, called anendemic pattern (e.g., Bali,Indonesia)

TRANSMISSION OF JE

JE is spread by mosquitoes.Culex tritaeniorhynchusis the main vector in most of Asia, but other species

that breed in rice paddies, ditches, and ground pools are also important.

JE Transmission Cycle

PEOPLE AT RISK

People living in rural areas have the highest risk of disease because themosquitoes that spread JE breed in rice paddies and pools of water.

Cases in urban areas also occur.Diagnosis: serologyNo specific therapy is available.Since Culex has a flight range of 20km, all local control measures will fail.

An effective vaccine is available.---------------------------------------------------------------------------------------------------------

YELLOW FEVER

Yellow fever virus:prototype member of Flaviviridae

Single serotype with 7genotypes (5 in West Africa and 2 in S. America)

Virus multiplies in manydifferent types of animalsand in mosquitoes

Grows in embryonated eggs, chick embryo cell cultures and cell lines,including those of monkey, human, hamster and mosquito origin.

After a period of 3-4 days, the more severely ill patients w/ a classical YFcourse will develop bradycardia (Fagets sign), jaundice, & hemorrhagicmanifestations.

50% of patients with frank YF will develop fatal disease characterized bysevere haemorrhagic manifestations, oliguria and hypotension.

Diagnosis: SerologyThere is no specific antiviral treatment

An effective live attenuated vaccine is available against yellow fever and

used for persons living in or traveling to endemic areas2 MAJOR FORMS:

1.URBAN YELLOW FEVERo Transmitted between humans by the Aedes aegypti mosquitoeso Classically Yellow Fever presents with chills, fever, and headache

Generalized myalgias and GI complaints (N+V).o Some patients may experience an asymptomatic infection or a mil

undifferentiated febrile illness

2. JUNGLE (SYLVATIC) YELLOW FEVER o Natural reservoir of the disease in a cycle involving nonhuman

primates and forest mosquitoes.o Man may become incidentally infected on venturing into jungleo Some patients may experience an asymptomatic infection or a mil

undifferentiated febrile illness.o Incubation period: 3-6 dayso S/sx: fever, chills, headache, dizziness, myalgia, backache, nausea

vomiting and bradycardia (fagets sign)o Infection may be so mild as to go unrecognized.o In 15%, the disease progresses to a more severe form, with fever,

jaundice, renal failure and hemorrhagic manifestations.o Severe stage (HEPATORENAL FAILURE): >20% mortality

(children, elderly)o Encephalitis is rareo Death: 7-10th day of illnesso Regardless of severity: no sequelae

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DENGUE VIRUS

Dengue: biggest arbovirus problem in the world today with over 2 milliocases per year

found in SE Asia, Africa and the Caribbean and S America4 serotypes (DEN-1, 2, 3, 4)Each serotype provides specific lifetime immunity, and short-term cross-

immunity All serotypes can cause severe and fatal disease

Classically presents w/ high fever, lymphadenopathy, myalgia, bone & jopains, headache, maculopapular rashSevere cases may present w/ hemorrhagic fever & shock w/ a mortality of

10% (Dengue hemorrhagic fever/shock syndrome)DHF & DSS appear most often in Pxs previously infected by a different

serotype of dengue, suggesting an immunopathological mechanism.Dx by serologyNo specific antiviral therapy is available.Prevention in endemic areas depends on mosquito eradication. The

population should remove all containers from their premises w/c may serve avessels for egg deposition.

A live attenuated vaccine is being tried in Thailand w/ encouraging


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Area infested with Aedes Aegypti

Area with Aedes Aegypti and dengueepidemic activity

Replication & Transmission of Dengue Virus

1. Virus transmitted tohuman in mosquito saliva2. Virus replicates in targetorgans3. Virus infects white bloodcells & lymphatic tissues4. Virus released &circulates in blood

5. Second mosquito ingests viruswith blood6. Virus replicates in mosquitomidgut & other organs, infectssalivary glands7. Virus replicates in salivary glands

Aedes aegypti MOSQUITO

Dengue transmitted by infected female mosquitoPrimarily a daytime feeder Lives around human habitationLays eggs and produces larvae preferentially in artificial containers

DENGUE CLINICAL SYNDROMES

Undifferentiated fever

Classic dengue fever Dengue hemorrhagic fever Dengue shock syndrome

UNDIFFERENTIATED FEVER

May be the most common manifestation of dengueProspective study found that 87% of students infected were either

asymptomatic or only mildly symptomaticOther prospective studies including all age- groups also demonstrate silent

transmission

CLINICAL CHARACTERISTICS OF DENGUE FEVER

Fever HeadacheMuscle and joint painNausea/vomitingRashHemorrhagic manifestations

Signs and Symptoms of Encephalitis/Encephalopathy Associated with

Acute Dengue Infection

Decreased level of consciousness:lethargy, confusion, comaSeizuresNuchal rigidityParesis

HEMORRHAGIC MANIFESTATIONS OF DENGUE

Skin hemorrhages:petechiae, purpura, ecchymosesGingival bleedingNasal bleedingGastro-intestinal bleeding:hematemesis, melena, hematocheziaHematuriaIncreased menstrual flow

Clinical Case Definition for Dengue Hemorrhagic Fever

4 Necessary Criteria:

Fever, or recent history of acute fever Hemorrhagic manifestationsLow platelet count (100,000/mm3 or less)Objective evidence of leaky capillaries:

o elevated hematocrit (20% or more over baseline)o low albumino pleural or other effusions

Clinical Case Definition for Dengue Shock Syndrome

4 criteria for DHFEvidence of circulatory failure manifested indirectly by all of the followin

o Rapid and weak pulseo Narrow pulse pressure (


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Persistent vomiting Abrupt change from fever to hypothermia, with sweating and prostrationRestlessness or somnolence

WARNING SIGNS FOR DENGUE SHOCK

HYPOTHESIS ON PATHOGENESIS OF DHF

Persons who have experienced a dengue infection develop serum antibodiesthat can neutralize the dengue virus of that same (homologous) serotype

In a subsequent infection, the pre-existing heterologous antibodies formcomplexes with the new infecting virus serotype, but do not neutralize the newvirus Antibody-dependent enhancement is the process in which certain strains of

dengue virus, complexed with non-neutralizing antibodies, can enter a greater proportion of cells of the mononuclear lineage, thus increasing virus production

Infected monocytes release vasoactive mediators, resulting in increasedvascular permeability and hemorrhagic manifestations that characterize DHFand DSS

TOURNIQUET TEST

Inflate blood pressure cuff to a point midway between systolic and diastolicpressure for 5 minutes

Positive test: 20 or more petechiae per 1 inch2 (6.25 cm2)

LABORATORY TESTS IN DENGUE FEVER

Clinical laboratory testso CBC--WBC, platelets, hematocrito Albumino Liver function testso Urine--check for microscopic hematuria

Dengue-specific testso Virus isolationo Serology

Virus isolation to determine serotype of the infecting virus: IgMELISA test for serologic Dx

DENGUE: MANAGEMENT

No hemorrhagic manifestationsand patient is well-hydrated:home treatmentHemorrhagic manifestations or hydration borderline: outpatient

observation center or hospitalizationWarning signs (even withoutprofound shock) or DSS:hospitalize

FluidsRest

Antipyretics (avoid aspirin andnon-steroidal anti-inflammatorydrugs)

Monitor blood pressure,hematocrit, platelet count, levelof consciousness

DENGUE VACCINE?No licensed vaccine at presentEffective vaccine must be tetravalentField testing of an attenuated tetravalent vaccine currently underwayEffective, safe and affordable vaccine will not be available in the immedia

future

DENGUE PREVENTIONCurrently the only effective way to avoid dengue infection in areas where tdisease is endemic or epidemic is to avoid being bitten by infected mosquitothrough the use of personal insect repellent and other insect barriers.

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Ang trans na ito ay inihahandog ng:

MICROBIOMAN (+ 1 )

From 1st row (L to R):Paulfie, Edo, Teacher From 2nd row (L to R):Nia, Nickie, Turay

s3 l16 flaviviridae

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