25. Flavivirus Flashcards
what is a well-known flavivirus?
yellow fever
describe the clinical features of yellow fever
PERIOD OF INFECTION:
- minor symptoms: headache, nausea, dizziness
Some can resolve infection but some progress to
PERIOD OF INTOXICATION:
- severe infection: jaundice, haemorrhage, malaise
- 50% recover, 50% die
what was the Yellow Fever Commission? what were the results?
to prove that yellow fever was transmitted by mosquitos
volunteers were bitten by mosquitos that had fed on yellow fever patients –> got mild disease but quickly recovered –> still insufficient evidence
what were the Mosquito Brigades?
fumigate mosquitos to eradicate disease in Panama –> it worked!
why did yellow fever remain in areas where they eliminated the mosquitos?
mosquitos were only a vector –> non-human primates are the stable and persistent reservoir
development of YFV vaccine (4 stages)
- isolated virus from yellow fever survivor
- grew virus in mice
- passaged in monkeys
- > 100 passages in chicken eggs to form 17D vaccine strain
describe the 17D vaccine strain of yellow fever
attenuated virus that can grow and replicate without pathogenesis –> but still had some neurotropism and viscerotropism
baltimore class of flavivirus?
class 4 (+RNA)
is flavivirus enveloped or naked?
enveloped
shape of flavivirus capsid?
icosahedral
size of flavivirus capsid?
40-60nm diameter
3 characteristics of flavivirus
- monopartite
- linear
- 9.6 - 12.3 kb
6 main viruses in flaviviridae family
- mosquito-borne flavivirus
- insect-specific flavivirus
- tick-borne flavivirus
- NKV flavivirus
- hepacivirus
- pestivirus
what does NKV mean?
no known vector flavivirus
biggest group of flavivirus?
mosquito-borne flavivirus
who does Japanese encephalitis affect?
Children and immunocompromised adults
who does West Nile encephalitis?
Elderly, immunocompromised, and chronically ill patients
what transmits the Japanese Encephalitis Virus?
mosquitos –> JEV = arbovirus
2 primary hosts of JEV
- birds
- pigs
1 incidental/dead-end host of JEV
Humans
number of JEV cases in humans each year? mortality?
30,000 - 50,000 cases in humans each year –> 25-30% mortality
4 symptoms of JEV
- fever
- headache
- vomiting
- neurologic symptoms
JEV treatment?
no treatment –> just supportive care
JEV vaccine?
either formalin inactivated or live attenuated
recommended for travel >1 month
describe encephalitis viruses
most are asymptomatic or cause non-specific febrile illness
who do encephalitis viruses affect?
children or young adults
4 symptoms of severe encephalitis viruses
- meningoencephalitis
- aseptic meningitis
- polio-like acute flaccid paralysis
- parkinsonian syndrome
age-specific incidence of JEV vs WNV
JEV more common in younger age and most people are sero-positive
WNV more common in older age and sero-positive is rare
what type of mosquito transmits JEV and WNV?
Culex mosquito
primary host of WNV?
birds
incidental/dead-end host of WNV?
humans + other mammals
who does WNV infect?
elderly/immunocompromised ppl
6 symptoms of WNV
- fever
- headache
- vomiting
- muscle weakness
- lower back pain
- neurologic symptoms
proportion of asymptomatic vs symptomatic cases
80% of cases are asymptomatic
20% of cases are symptomatic and develop into neuroinvasive disease
treatment of WNV?
no treatment, not even vaccine
how is the spread of WNV measured
regular monitoring of bird sera
what type of mosquitos is Dengue Virus transmitted by?
Aedes mosquitos
primary host of DENV?
humans
8 symptoms of DENV
- fever
- headache
- vomiting
- abdominal pain
- low BP
- tachycardia
- seizures
- encephalitis
treatment of DENV?
no treatment, not even vaccine
5 stages in DENV clinical progression
- mosquito bite
- viraemia
- fever
- shock hemorrhage
- antibodies increasingly produced
what kills people when they get DENV? % lethality?
Dengue Hemorrhagic Fever/Dengue Shock Syndrome –> 50% lethality
how has the distribution of DENV subtypes throughout the world changed over time?
certain subtypes were only in certain areas, but now all 4 genotypes are everywhere
what type of mosquitos transmit Zika Virus?
Aedes mosquitos
6 symptoms of ZIKV
- fever
- maculopapular rash
- headache
- joint and muscle pain
- edema
- vomiting
tropism of ZIKV
nerve cells –> affects myelin
recent ZIKV outbreaks lead to: (2)
- Guillain-Barre syndrome
- Fetal microcephaly
treatment of ZIKV?
No treatment, but working on antibodies and vaccine
2 challenges in studying ZIKV in lab
- no pathogenicity in mice
- can only grow in vitro if antiviral defenses are removed, but this doesn’t give full picture of virus
challenge in diagnosing ZIKV
diagnosed thru PCR –> hard in 3rd world country where rapid diagnostics are better
describe flavivirus genome organization
5’ UTR and cap, structural proteins, non-structural proteins, 3’ UTR
how many ORF in flavivirus genome?
1 ORF with structural and non-structural regions
3 structural proteins
- C (core)
- prM/M (membrane)
- E (envelope glycoprotein)
6 non-structural proteins and functions
- NS1, NS2A, NS4A (RNA replication complex proteins)
- NS3 (protease/helicase/NTPase)
- NS4B (membranous web)
- NS5 (RdRP, guanyltransferase, methyltransferase)
what are the only 2 enzymes of flavivirus?
NS3 and NS5
relationship btwn NS2A and NS3
NS2A associates with NS3 as cofactor to help cleavage activity
why is NS5 a guanyltransferase?
allows G nucleotide to be added at 5’ end
why is NS5 a methyltransferase?
allows methylation once G is added at 5’ end
describe an immature flavivirus
upon assembly, has 60 copies of trimer envelope protein
describe production of mature flavivirus from immature flavivirus (4 steps)
- Immature virus is formed in vesicle in transgolgi
- pH in vesicle changes
- 60 copies of trimer of envelope protein becomes 90 copies of dimer of envelope protein
- membrane protein precursor is cleaved by furin, causing structural change into mature
describe flavivirus life cycle (6 steps)
- enters by endocytosis
- in low pH endosome, fusion proteins exposed to allow virus protein to fuse with endosome envelope
- +RNA translated into polyprotein
- polyprotein cleaved by NS3
- making mature enzymes that make -RNA for replication
- virus assembles, matures, and is released
what residue is crucial on fusion peptides?
Histidine
describe how pH changes histidine
histidine has ring where <pH 6 it is protonated and charged –> changing conformation of protein
how does histidine affect viral entry?
In acidic endosome, His287 and His438 are protonated allowing for fusion protein to change conformation to allow fusion
how does histidine affect virus maturation?
In acidic vesicle in trans-golgi, His323 and His146 are protonated to allow change from trimer to dimer for maturation
what is the role of furin?
allows maturation of membrane protein
what facilitates flavivirus replication?
genome circularization
how does genome circularization occur?
5’ and 3’ ends are brought together by base-pairing (H bonds)
how does replication begin?
stem loop A allows RdRP to bind and begin replication, with methylated cap acting as primer
flavivirus replication induces ____ and ____
flavivirus replication induces vesicle packets and convoluted membranes
where do vesicle packets and convoluted membranes derive from?
from rough-ER
what are vesicle packets and convoluted membrane?
sites of replication
why do vesicle packets have pores?
exit site for newly synthesized viral RNA
describe the assembly of flavivirus
occurs next to pores of vesicle packets –> virions stack within lumen of VP-containing ER network then leave via golgi
what is DENV antibody-dependent enhancement?
people who are reinfected get increased severity of infection
why does antibody-dependent enhancement occur? 3 results
antibodies from first infection recognize different DENV and allow internalization
- leukocytes and BBB cells infected
- inflammation and cytokine storm
- compromises CNS function
