Lec 14: Dengue Virus

Flavivirus Replication 1

-uses RNA-dependent RNA polymerase

-Cytoplasmic genome replication and protein synthesis

-(+) strands used as mRNA

Flavivirus Replication 2

• -produces nested subgenomic RNAs

  -assembly occurs in the endoplasmic reticulum

  -release via exocytosis

Flavivirus genus: Structure, genome, and phylogeny

• Flaviviruses are +ssRNA viruses that replicate in the cytoplasm and use the polyprotein translation strategy

• Flavivirus NS1 is a secreted virulence factor that can cause endothelial dysfunction in the tissue where pathology occurs in human disease

The Flavivirus genus consists of small, enveloped, positive-sense RNA viruses (approx. 11 kb) that cause significant human disease, including Dengue, Zika, and West Nile. They feature a single open reading frame flanked by highly structured untranslated regions, encoding a polyprotein processed into 3 structural and 7 non-structural proteins. Phylogenetically, they diverge into mosquito-borne, tick-borne, and non-vector-borne clusters

Structural for Flavivirus

Capsid (C), Membrane (prM) and Evvelope (E)

Non-structural of Flavivius

NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5

Why is NS1 essential for flaviviruses such as dengue, Zika, and West Nile

It is needed for viral replication within host cells, and it acts as a virulence factor (can infect a host) by disrupting vascular integrity and plays a key role in immune evasion. The NS1 is in the ER where it rearranges host membranes to form replication compartments and facilitating viral RNA replication.

Bc NS1 is secreted at high levels in the serum early during infection (prior to antibody development) it is a vital marker for early detection in dengue and Zika infections

How has Denv co-circulated?

DUe to increased international trade and travel increased co-circulation of all 4 DENV serotypes. While the greatest risk factor for severe dengue is prior infection with a different DENV serotype (distinct variation within a microbial species (bacteria or viruses) classified based on specific surface antigens such as cell surface proteins)

Dengue Fever (DF)

-high feer

-headache

-Retro-orbital pain

-nausea, vomiting

-cutaneous rash

-Hemorrhagic

manifestations

-(Thrombocytopenia)

Dengue Hemorrhagic fever/ Dengue Shock syndrome (DHF/DSS)

-increased vascular permeability

-Hemoconcentration

hypovolemic shock

gemorrhagic manifestations

-(Thrombocytopenia) (<100,000 platelets/ml)

-abdominal pain

-Cytokin storm, many cytokines elevated in serum

-little or no damage to vascular endotehlium

Integral hyptothesis of Dengue

Individual Risk factors

-Age, race, gender, nutritual status, chronic illness, immune status

Epidemiological Risk factors

-# of susceptibles

-vector density

-virus circulation

-antibody-dependent enhancement

Viral Risk factors

-serotype

-genotype/clade

-NS1

Filo viruses

GP1 and GP2 are structural components of the G protein which GP1 functions as attachment and GP2 is what fuses. sGP decoy (Vp35) can be made and released leading to lots of immune response which is why we see hemorrhage, also Vp24 inhibits stat1

Genome: -ssRNA

Entry: Nonspecific internalization of large amounts of liquid in large endocytic vesicles “called macropinosomes”

Replication strategy: Start and stop subgenomic rna

Translation strategy: Standard translation, the different GP expression is primarily in stop sequence overlooking in transcription

Prevention/treatment: Supportive, some vaccine attempts

Disease: Ebola

Orthomyxo

Hemaggluntinin for receptor binding and membrane fusion "*neuraminidase for virion release and presenting direct infection of neighboring cell

Genome: -ssRNA segmented *IN THE NUCLEUS

Entry: Viral HA binds sialic acid on surface of host cell

Replication strategy: Snatched the 5’ cap from a paused transcript from RNA pol2. Makes mRNA and undergoes splicing in the nucleus to create different transcripts

Translation strategy: Cap snatching

Prevention/treatment: Yearly vaccine, supportive care

Disease: Influenza/flu

Arenavirus

NO poly A tail

Genome: Ambisense (+ and -)

Entry: RME

Replication strategy: Has long and short genome which is half (-) and half (+) that is transcribed up to the hairpin or with abundant NP read through

Translation strategy: Cap-snatching but done with the L protein packaged in the virion which is different from influenza

Prevention/treatment: No therapeutics one vaccine attempted

Disease: Lassa fever from rats. Can cause hemorhagic or non-pathogenic infection in humans