CSB351Y1 Lecture Notes - Lecture 27: Viral Hemorrhagic Fever, Tourniquet Test, Viremia
Lecture 27: Flaviviridae 2
Dengue Fever Virus
• Icosahedral, ssRNA, enveloped, 50nm diameter, origin unknown, highly adapted to mosquito hosts, humans first
came in contact with DFV when forests cleared for human settlements (jungle → human populations)
• 3 structural proteins (nucleocapsid (c), membrane associated protein (M) and envelope protein (E)) responsible
for neutralization, fusion, interaction with virus receptors = associated with E protein
Replication Cycle
• Entry (receptor binding) by endocytosis, E protein fuse to membrane of endosome, release RNA, transcription (-
sense), polyprotein processing → protease cleavage in host membrane/ER → genome packaging (+ sense) with
capsid proteins on surface of ER, prM and E associated with inside of ER → immature virus particle → prM
conformation change that clips → mature virus particle
• Dimeric or trimeric conformation of E glycoprotein
• prM (precursor membrane protein) – associated with domain II of E protein and acts as chaperone for folding E
and preventing premature fusion of virus
- Contains furin protease cleavage site – cleaved into c-terminal M portion (transmembrane domain remains
with virus) and n-terminal fragment dissociates upon release of virus from infected cell
Epidemiology
• Exist in nature – forest cycle involves canopy-dwelling mosquitoes and primates, rural cycle has Asia and Pacific
humans and urban cycle (most important for us)
• Transmission – bite mosquito – all 4 serotypes cause high levels of viremia (virus also acquired by mosquitos)
• No apparent effect on mosquito (life long infection however) but female mosquitoes transmit transovarily (eggs)
• Distribution and host range – worldwide tropics, southern Saharan Africa, half million hospitalized (children)
• No vaccine or antiviral drug available
4 grades of DHF (dengue hemorrhagic fever)
1. Fever and nonspecific symptoms, positive tourniquet test is only hemorrhagic manifestation
2. Grade 1 + spontaneous bleeding
3. Signs of circulatory failure (rapid/week pulse, change in blood pressure, hypotension, cold/clammy skin)
4. Profound shock (no heart pulse and blood pressure goes down – near death)
Viral Risk Factors of DHF Pathogenesis
• Virus genotype – epidemic potential: how much virus in blood (viremia level), infectivity (how much mosquitos)
• Virus serotype can determine how sick you can be – DHF risk is greatest for DEN-2, DEN-3, DEN-4 and DEN-1
Tropism (which tissues are affected)
• Primary virus replication site in phagocytic monocytes (immune cell) → liver, lungs, kidney, lymph, stomach
• Encephalopathy reported but dengue viruses cannot cross BBB into CNS; DHF or DSS (dengue shock syndrome)
Antibody-dependent enhancement (ADE)
• DHF, develop immune (antibodies) for subtype to prevent virus binding to macrophage cells of host to gain entry
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