Dengue virus Flashcards
What are arboviruses?
RNA viruses spread by moquito, tick or fly bites
What is Dengue virus?
- positive ssRNA virus spread by mosquitoes
- 4 serologically distinct groups 1-4
- causes the most important arthropod-bourne viral disease of humansWh
What family is Dengue virus from?
- Falviridae
- related to Zika virus and has some cross-reactivity
What is the worldwide distribution of Dengue virus?
- countries at risk of infection directly correlate with where mosquito vectors live
- rang constantly expanding as temperatures rise
How is Dengue virus transmitted?
- spread between mosquitoes and primates
- mosquito bites a human and the cycle of humans and mosquitoes infecting one another begins
What are the two types of Dengue virus?
- Dengue / dengue fever
- severe dengue (progression of dengue fever)D
describe the clinical features of dengue fever
- fever headache, aches and pains
- acute phase 3-7 days
- can be prolonged and lead to tiredness and symptoms seen in long covid
- acn sometimes progress to severe dengue
Describe the clinical features of severe dengue
- usually in children
- acute phase the same as Dengue fever
- fever gives way to sudden circulatory collapse
- increase in vascular permeability leads to fluid leakage into the lungs and tissues
- can cause shock and death less than a day after first symptoms occur
What is the structure of a flavivirus such as Dengue?
- viral envelope embedded with M + E proteins
- nucleocapsid comprised of viral RNA + a c protein at the 5’ end of the genome
What is the genome organisation of a flavivirus such as Dengue?
- structural genes at 5’ (C, M and E)
- non structural include NS1, NS2 protease, NS4 polymerase
How does Dengue virus enter the host cell?
- receptor mediated endocytosis
- endosome acidified and virus nucleocapsid is released into the cytoplasm
Where does Dengue virus replicate and mature?
- replication complex is formed at the ER membrane
- packaged by the core protein and assemble at the ER
- matures as it travels through the golgi
- rearrangement of strucutral proteins prevents fusion with cell membranes before the virus exits
How and where does the proteolytic processing of the polyprotein occur?
- polyprotein is threaded through the ER as it is translated
- capsid and replication proteins on the cytoplasmic side
- others in the ER lumen
- cleavage by NS2B
Why is Dengue virus difficult to study?
- mice are ok for drug testing byt they dont respond to the virus like humans do
- primates show no symptoms
- studies must be done on epidemiological data and human volunteers
What cells are the initial major target for Dengue virus?
- skin dendritic cells
- enter the blood and reach their major targer: monocytes and macrophages
- virus has also been isolated from lung, kidney, lymph nodes and more
How does dengue virus appear to cause cell death?
- not killed by the virus itself
- capillary leakage may be host cytokine mediated
What is a second infection with a different serotype of Dengue like?
- sequential infections are more likely to result in severe disease
- immune enhancement hypothesis
- pre-existing cross-reactive antibodies actually allow for worsened infection
- damage by activated CD8+ T cells
How does Dengue viral load affect disease severity?
- high viral lead increases severity
- dengue 2 is most virulent
- strains exist within Dengue 2
What 3 things do cells infected with Dengue release? What do host antibodies respond to for each?
- mature virions have their envelope protein targetted
- immature virions have their pre-M protein targeted
- NS1 protein has antibodies specific to NS1 targetting it
What does the immune system usually do in response to mature Dengue virions?
- produces antibodies specific for envelope proteins
- can lead to neutralisation by blocking uncoating, entry etc
- can also lead to antibody-dependent enhancement
What does the immune system do in response to immature dengue virions?
- antibodies specific for pre-M
- can lead to antibody dependent enhancement in secondary infeciotn
What is antibody dependent enhancement?
- in secondary infection, cross-reactive, non-neutralising antibodies bind the virus
- virus/ab complex can bind fc receptors on monocytes and macrophages and have enhanced virus uptake in these cells
Where are the epitopes on the Dengue polyprotein that are recognise by T cells?
- all across the protein
- mostly on NS3
What is the role of CD4 T cellls in Dengue infection?
recognise antigens on mature virions, immature virions, NS1 and the polyprotein via MHC II and produce cytokines
What is the role of CD8 T cells in dengue infection?
recognise antigens on mature virions, immature virions, NS1 and the polyprotein via MHC I and induce target cell lysis
How can cross-reactive T cells worsen secondary Dengue infection?
- different serotypes have different but similar epitopes
- if T cells only have partial recognition of antigens it can lead to an aberrant T cell response
- insufficient cell lysis due to low levels of IFN-Y and TNF
- worsened infection
What are some immune factors of severe dengue?
- multifactorial and not fully understood
- inflammatory mediates co-indice with vascular leakage - hallmark of severe disease
- neutrophil degranulation
How has global distribution of Dengue serotypes changed?
- spread from parts of Africa and Asia to much larger surrounding areas
- large area around the equator growing
- Dengue 1-4 are seen in all affected regions now
What leads to an increased probability of severe Dengue?
- increased transmission and worldwide movement increases the probability of virulent strain selection
- increased probability of secondary infection leads to increased probability of immune enhancement
What are some challenges in developing a Dengue virus vaccine?
- immune enhancement means that inducing immunity for one serotype could worsen infection with others - need a tetravalent vaccine
- lack of suitable animal model
- many commonly affected countries can’t afford expensive vaccines and drugs
What vaccine methods seem most promising at the moment and are in trials?
- recombinant live-attenuated vaccine in those who have had Dengue before
- a chimeric recombinant virus whereby yellow fever is cloned and the structural genes are replaced with those of all 4 types of Dengue virus
- could also use a dengue virus back bone?
How can vectors be controlled to control the spread of dengue virus?
- release of Wolbachia sp.
- bacterial symbiote of mosquitoes that decreases female life span by 50%
- release in Indonesia lead to a 77% decrease in Dengue and fewer hospital admissions
