Lecture 30 - Flaviviruses Flashcards
Where do arboviruses replicate?
In arthropod vector and animal host
Are humans the preferred host for most arboviruses?
No. Incidental hosts. Except for yellow fever and dengue
Example of a DNA arbovirus
None. All arboviruses are RNA
Viral families that can be arboviruses 1) 2) 3) 4)
1) Reoviridae 2) Flaviviridae 3) Togaviridae 4) Bunyaviridae
Types of togaviruses that can be arboviruses
Alphaviruses
Flavivirus genome
Type of gene product of flaviviruses
Polyprotein
Immature vs mature flavivirus virion structure
Immature - PrM protein intact, in the ER. Mature, infectious- Pr protein cleaved from M protein. M and E proteins are joined. Flat capsid shape.
Number of prM and E copies in a flavivirus capsid
180
What happens once pr is cleaved from M on a flavivirus virion?
M and E form homodimers.
Flavivirus replication 1) 2) 3) 4) 5) 6)
1) Receptor-mediated endocytosis. 2) Flavivirus envelope fuses with endosome, releasing genome into cytoplasm 3) Translation, proteolytic processing of polyprotein. This occurs on ER cytoplasmic membrane 4) Non-structural proteins formed, viral RNA replication. 5) Virions assembled on ER membrane. 6) Virions bud from ER, exocytosed through Golgi.
Do flaviviruses have a virion polymerse?
No. They are +RNA viruses
Number of denguevirus types
Four
Is dengue infection localised or systemic?
Systemic, high viremia
Similarity of denguevirus types
Not very similar. As dissimilar to one another as other flaviviruses are. Don’t confer neutralising antibodies
Primary flaviviral antibody target
E surface protein (envelope protein)
Dengue transmission cycle
Extrinsic incubation period - Time between mosquito acquiring virus and becoming infectious. Normally 7-10 days. Intrinsic incubation period - When the mosquito can be transmitted to humans from infected mosquito.
Implications of a 7-10 day extrinsic incubation period
Infected mosquito can only transmit virus 7-10 days after blood meal that infected it.
Most important denguevirus vector
Aedes aegypti
Denguevirus genetic bottleneck
Needs to be able to replicate both in humans and mosquitoes
Aedes aegypti features 1) 2) 3) 4)
1) Prefers laying eggs in artificial containers (EG: tyres, empty drink cans) 2) Adults tend to rest on surfaces inside homes 3) Daytime biting, preference for humans 4) Once infected, mosquito is infected for life
Areas with the greatest dengue burden
India, SE Asia, South America
Global dengue burden
100 million symptomatic cases 2.1 million severe cases 21,000 deaths
Outcome of most dengue infections
Clinically silent
Mild dengue symptoms 1) 2) 3) 4) 5) 6) 7)
1) Fever 2) Headache 3) Myalgia 4) Retro-orbital pain (very characteristic of dengue) 5) Vomiting 6) Anorexia 7) Joint pain
Severe dengue symptoms 1) 2) 3)
1) Severe plasma leakage into interstitial tissue 2) Severe haemorrhage 3) Severe organ impairment
Most common severe symptom of dengue
Severe plasma leakage
What might lead to severe plasma leakage in severe dengue infections?
Thought to be from immune response. Critical stage is at day 4-6 of disease, when dengue viremia is in steep decline.
What can vascular permeability in dengue lead to?
Dengue shock syndrome
Risk factors for dengue shock syndrome 1) 2) 3) 4) 5)
1) Secondary infection with another dengue type 2) Young age 3) Female gender 4) Obesity 5) Maybe virus strain
Why is being infected with a secondary denguevirus strain more severe?
Denguevirus antibody-dependent enhancement
Denguevirus antibody-dependent enhancement
Preexisting antibodies to another dengue strain bind but fail to neutralise virus. Results in greater uptake of dengue virions by macrophages, and increased viral replication
Challenges for dengue vaccine 1) 2) 3)
1) Infection with one dengue serotype only confers lifelong immunity to that one serotype 2) Longer vaccine followup for boosters required, because of possible severe heterotypic infection 3) Lack adequate animal disease models (can infect animals, but animals don’t develop the same symptoms
Flavivirus E glycoprotein function
Binds to host cell receptor. Mediates virus-specific membrane fusion
Manufacturer of dengue vaccine in stage 3 trials
Sanofi-Pasteur
Outcome of Sanofi-Pasteur stage 3 denguevirus vaccine trial
56.5% efficacy in preventing symptomatic infection
Design of Sanofi-Pasteur denguevirus vaccine
CYD-TDV is a tetravalent vaccine. Yellow fever 17D (attenuated) vaccine strain has PrM and E proteins replaced with those dengue
Denguevirus treatment 1) 2) 3)
1) No licensed vaccine, no specific treatments 2) Analgesics (avoid ibuprofen, aspirin) 3) Avoid dehydration 4) Avoid mosquito bites
Effect of Wolbachia infection of Aedes aegypti
Decreases mosquito susceptibility to denguevirus infection Infected male can’t mate with uninfected female. Infected males and infected females can produce offspring. Uninfected males and infected females can produce offspring. All offspring are infected with Wolbachia
Yellow fever 1) 2) 3) 4)
1) Flavivirus 2) Causes haemorrhagic fever 3) Transmitted by bite of female mosquito of genera Aedes, Haemogogus, Sabethes 4) Maintained in nature in cycles of mosquitoes and sylbatic hosts (non-human primates)
Is there a yellow fever vaccine?
Yes. 17D live attenuated strain. One dose gives immunity for 10 years.
Yellow fever incidence
~200,000 cases.
Yellow fever mortality
15-20%
Where is yellow fever found?
Tropical, subtropical regions of Africa, Sough America
Yellow fever symptoms 1) 2) 3) 4) 5)
1) Early symptoms are muscle pain, fever, headache 2) Toxic phase is where damage occurs to the liver, kidneys, heart. 3) Viremia is only in first 3 days of infection 4) In severe cases, jaundice, kidney failure, internal bleeding, circulatory collapse 5) Death in 6-7 days post-infection
Yellow fever treatment
Only supportive therapy
