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Flavivirirus

Flavivirirus

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Microbiology (Dra Madrid/Reyes)Flaviviridae13 December 07
FLAVIVIRIDAE
Flaviviridae family
o
Genus
Flavivirus
Once classified in the Togaviridae, nowconstitutes one of three genera in the familyFlaviviridae
o
Genus
Pestivirus
Includes animal pathogens (bovine viraldiarrhea and hog cholera viruses) that are of considerable economic importance, but containsno known human pathogens
o
Genus
Hepacivirus
o
All flaviviruses that cause disease in humans arearthropod-borne viruses (arboviruses)
VIRUSPRIMARYVECTOR VERTEBRATERESERVOIGEOGRAPHICDISTRIBUTION
Dengue1,2,3,4
 Aedes aegypti 
Humans,monkeysTropicsJapaneseenceph
Culex 
BirdsAsiaSt. Louisenceph
Culex 
Birds, pigsAmericasWest Nile
Culex 
BirdsAfrica, tropicalAsia,MediterraneanYellow Fever
 Aedes aegypti 
Humans,monkeysTropical Africaand theAmericasOmskhemmorhagicfever
Dermacentor 
RodentsCentral RussiaTick-borneencephalitis
Ixodes
Rodents,birds,domesticated animalsRussia, EasternEurope,ScandinaviaLouping III
Ixodes
Sheep,birdsBritish IslesPowassan
Ixodes
SmallmammalsCanada, US,RussiaKyansanurForestDisease
Haemaphysalis
RodentsSouthwestIndiaMurray Valleyencephalitis/Kunjin Rocio
Culex 
Birds Austrialia, NewGuniea
VirusDisease
Dengue 1,2.3.4Fever, rash, arthralgia, myalgiaJapanese encephEncephalitisSt. Louis encephEncephalitisWest NileFever, rash, arthralgia, myalgiaYellow FeverFever, hemorrhage, jaundiceOmsk hemorrhagic feverFever, hemorrhageTick-borne encephalitisEncephalitisLouping IIIEncephalitisPowassanEncephalitisKyansanur Forest DiseaseFever, hemorrhage, encephalitisMurray Valleyencephalitis/Kunjin RocioEncephalitis 
PATHOGENIC FLAVIVIRUSES
3 groups according to symptoms they cause
o
Meningoencephalitides
SLE, JE, MVE and TBE
o
Fever-arthralgia-rash syndrome
DEN, WN, KUN
o
Hemorrhagic fever syndrome
Omsk hemorrhagic fever, Kyasanur Forest dsevirus, YF, DEN
FLAVIVIRUS STRUCTURE
Virions: spherical, 40-50 nm in diameter
Nucleocapsid contains capsid protein (C)
RNA: single 405 (10.9 kilobases) positive-sense strand
o
Capped at the 5’ end, but, unlike alphaviruses, hasno poly A segment at the 3’ end
Envelope: lipid bilayer
o
1) envelope protein (E) [51,000-59,000 daltons]
o
2) small nonglycosylated protein (M) [8,500daltons]
o
Only E, which is glycosylated in most flaviviruses, isclearly demonstrable on the virion surface
Virions mature at intracytoplasmic membranes
Most members are transmitted by bloodsuckingarthropods
FLAVIVIRUS GENOME
Upon translation, several enzymes cut single polypeptideinto functional protein units.
Structural
protein functions:
C:
highly basic component of the nucleocapsid
prM:
precursor of M protein
M protein:
membrane-associated and serve amatrix function, linking capsid and envelope
E:
major envelope protein; virion assembly, receptorbinding and membrane fusion
MULTIPLICATION
Genomic RNA is capped (not polyadenylated) and servesas mRNA for all proteinds
Structural proteins are encoded at the 5’ end of thegenome; nonstructural proteins (e.g., RNA-dependentRNA polymerase) are encoded in the 3’ two-thirds
Complementary (antisense) RNA, made from genomicRNA, serves as a template for progeny genomic RNA
(+) Strand parental RNA(-) StrandRNA(+) Strand progeny RNA
Progeny virus
 
Leu, virns, brim, ate candz1 of 6
Nonstructural proteinsencoded in the 3’ end of genome RNAProteins encoded inthe entire genomeStructural proteinencoded in the 5’
 
Microbiology –
Flaviviridae
by 
 Dra Madrid/Reyes
Page
2
of 6
FLAVIVIRUS REPLICATION
Replication occurs in the cytoplasm (20-30 hrs)
Entire virus genome is translated as a single polyproteinwhich is then cleaved into the mature proteins
o
Structural proteins: encoded at the 5’ end
o
Nonstructural proteins (e.g., NS-1 and RNA-dependent RNA polymerase) are encoded in the 3’ two-thirds
Complementary negative strand RNA is synthesized byNS proteins and then is used as a template for genomicprogeny RNA synthesis
Assembly occurs characteristically into cytoplasmicvacuoles (in association with Golgi or smoothmembranes)
Release occurs when cell lyses
FLAVIVIRUS PATHOGENESIS AND CLINICALMANIFESTATIONS
Flaviviruses vary widely in their pathogenic potential andmechanisms for producing human disease
It is useful to consider them in three major categories
o
Those associated primarily with the encephalitisSyndrome (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 by deposition of virus throughthe skin via the saliva of an infected arthropod
Replicates locally & in regional lymph nodes
viremia
Most human infections with St. Louis enceph (SLE) andJapanese enceph (JE) viruses, there is either no apparentdisease or a nonspecific febrile illness with headache
Infection resolves, and lasting immunity is produced
CNS lesions may develop: aseptic meningitis orencephalitis
In the great majority of flavivirus infections, virus iscleared by the immune system
o
However, persistence in neurological tissue hasbeen noted with tick-borne encephalitis viruses, andrecent reports of recurrent encephalitic bouts inchildren have been associated with JE virusrecovery from peripheral blood mononuclear cells
HOST DEFENSES
Lasting protection is generally restricted to the sameflavivirus, and is associated with neutralizing antibodies
ANTHROPOD-BORNE VIRUSES
Anthropod-borne viruses (arboviruses) WHO definition: “Viruses maintained in nature principally throughbiological transmission between susceptible vertebratehosts by haematophagus arthropods.” 
Arboviruses belong to three families1.Togaviruses
-
e.g. EEE, WEE, and VEE2.Bunyaviruses- e.g. Sandfly Fever, Rift Valley Fever, Crimean-Congo Haemorrhagic Fever3.Flaviviruses
-
e.g. Yellow Fever, Dengue, JapanesesEncephalitis
TRANSMISSION CYCLES
Man-arthropod-man
o
e.g. Dengue, Urban yellow fever
o
Reservoir may be in either man or arthropod vector
o
In the latter transovarial transmission may takeplace
Animal-arthropod vector-man
o
e.g. Japanese encephalitis, Jungle yellow fever
o
Reservoir is in an animal
o
Virus is maintained in nature in a transmission cycleinvolving the arthropod vector and animal. Manbecomes infected incidentally.
Both cycles may be seen with some arboviruses such asyellow fever
ARTHROPOD VECTORS
Mosquitoes
o
Japanese encephalitis, dengue, yellow fever, St.Louis encephalitis
Ticks
o
Various tick-borne encephalitides etc.
ANIMAL RESERVOIRS
In many cases, the actual reservoir is not known. Thefollowing animals are implicated as reservoirs
o
Birds: Japanese encephalitis, St. Louis encephalitis
o
Pigs: Japanese encephalitis
o
Monkeys: Yellow Fever
o
Rodents: Russian Spring-Summer encephalitis
DISEASES CAUSED
Fever and rash
o
This is usually a non-specific illness resembling anumber of other viral illnesses such as influenza,rubella, and enterovirus infections. The patientsmay go on to develop encephalitis or haemorrhagicfever
Encephalitis
o
St. Louis encephalitis, Japanese encephalitis
Haemorrhagic fever
o
e.g, Yellow fever, dengue
DIAGNOSIS
Serology – usually used to make a diagnosis of arbovirusinfections
Culture – a number of cell lines may be used, includingmosquito cell lines. However, it is rarely carried out sincemany of the pathogens are group 3 or 4 pathogens
Direct detection tests – e.g. detection of antigen andnucleic acids are available but again there are safetyissues
PREVENTION
Surveillance – of disease and vector
Control of vector – pesticides, elimination of breedinggrounds
Personal protection – screening of houses, bed nets,insect repellants
Vaccination – available for a number of arborealinfections e.g. Yellow fever, Japanese encephalitis,Russian tick-borne encephalitis
JAPANESE ENCEPHALITIS
First discovered and originally restricted to Japan. Nowlarge scale epidemics occur in China, India and otherparts of Asia.
Flavivirus, transmitted by culex mosquitoes
The virus is maintained in nature in a transmission cycleinvolving mosquitoes, birds and pigs.
Most human infections are subclinical, the unapparent toclinical cases is 300/1.
In clinical cases, a life-threatening encephalitis occurs.
The disease is usually diagnosed by serology. No specifictherapy is available.
Since culex has a flight range of 20km, all local controlmeasures will fail. An effective vaccine is available.
 
Microbiology –
Flaviviridae
by 
 Dra Madrid/Reyes
Page
3
of 6
VIROLOGY
Japanese encephalitis (JE) serocomplex
o
10 viruses
o
6 human pathogens
(JE, West Nile, Kunjin,Usutu, St. Louis Encephalitis, Murray ValleyEcephalitis viruses)
o
Most are amplified bird – mosquito – bird
5 genotypes in Asia
(most isolates in genotype 1)
HISTORY OF DISCOVERY
1871: “Summer encephalitis” epidemic in Japan
1924: Agent from human brain tissue isolated in rabbits
1934: Isolate of this virus produced experimentalencephalitis in monkeys
1938: First isolate from Culex tritaeniorhynchus
1930s: First mouse brain-derived vaccines developed
1954: “Refined” mouse brain vaccine developed
WHY IS JE A PROBLEM?
JE
is the
leading cause of viral encephalitis in Asia
,now that poliomyelitis has nearly been eradicated.
More than 3 billion people live in areas where JE arereported to WHO each year.
10,000 to 15,000 deaths are reported each year.
CASES ARE UNDER-REPORTED
Cases are under-reported due to
o
Lack of good surveillance
o
Lack of diagnostics
Actual number of cases is probable more than 175,000per year
CLINICAL SPECTRUM OF JE DISEASEDEATH AND DISABILITY FROM JE
Up to 30% of all patients with JE die
For those that survive the illness, 30% to 75% cases areleft with disability
Disability is with both physical and cognitive
AGE GROUPS AFFECTED BY JE
Children 1 to 15 years of age are mainly affected inendemic areas.
But people of any age can be affected. Adult infectionmost often occurs in areas where the disease is newlyintroduced.
DIFFERENT PATTERNS OF AGE DISTRIBUTION CASESTWO PATTERNS OF TRANSMISSION OF JE
1.Seasonal, called an epidemic pattern (e.g., southernChina)2.Year-round, called an endemic pattern (e.g., Bali,Indonesia)
TRANSMISSION OF JE
JE is spread by mosquitoes
Culex tritaeniorhynchus
is the main vector in most of Asia, but tohe species that breed in rice paddies, ditches,and ground pools are also important.
MildAsymptomatiModeratSeverDie

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