HostR Lecture 8, W4.

The dengue virus belongs to the Flaviviridae family of viruses.
It has a diameter ranging from 40 - 65 nm.
Structure details:
- Enveloped with an icosahedral nucleocapsid.
- Contains (+)ssRNA, which acts as mRNA once introduced into host cells.
- The genome is approximately 10,000 - 11,000 bases in length.
Transmission occurs primarily through mosquitoes or ticks, predominantly in tropical and subtropical regions.

There are 4 serotypes of dengue virus circulating among humans.
The dengue virus (DENV) is responsible for dengue fever (DF), commonly known as breakbone fever, due to severe pain associated with the illness.
More severe manifestations include dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS).
It's estimated that there are between 100 - 400 million dengue infections annually, with 67 - 136 million cases manifesting clinically.
There are currently no antiviral drugs available specifically for treating DENV disease. Treatment is primarily palliative, focusing on symptom management.
The efficacy of the current vaccine is suboptimal and may actually increase disease severity.
Dengue can lead to significant mortality, killing one person approximately every 12 minutes and is a leading cause of death among children,
As a fast-spreading and epidemic-prone infectious disease, dengue threatens 4 billion people across 128 countries.

Aedes aegypti mosquitoes are the primary carriers of both yellow fever and dengue virus.
These mosquitoes are diurnal, meaning they are more active during the day.
Only female mosquitoes bite, as they require blood to lay eggs, and they breed in stagnant water.

Effective prevention relies on controlling mosquito populations to limit human infection.
Strategies include:
- Managing stagnant water sources to reduce breeding grounds for mosquitoes.
- Personal protective measures: wearing light colors and long sleeves, and using insect repellent.
- Government interventions, including spraying insecticides in urban areas to control mosquito numbers.
- Source reduction: removal of debris and containers that collect water, thereby preventing mosquito breeding.
Caution: mosquitoes have adapted to urban environments and can breed in very small amounts of water.
A mosquito's lifecycle, transitioning from egg to larva, pupa, and finally adult can occur within 7 to 10 days.
For individuals infected with dengue virus, it is crucial to ensure hydration and rest due to fluid loss associated with hemorrhagic symptoms, as severe cases can lead to shock, which is life-threatening.
- The fatality rate from dengue is generally less than 1%.

Human activities contribute significantly to the rise in dengue cases, reflecting our role in facilitating the spread of the virus.

Infection begins when an infected mosquito bites a person.
The dengue virus targets Langerhans cells, a type of dendritic cell located in the skin, initiating the infection.
- These infected cells produce interferons as part of the immune response to limit the spread of the virus.
The virally infected Langerhans cells migrate to lymph nodes, where they infect additional cells, facilitating further viral spread.
As the dengue virus propagates, the result is viremia, a condition characterized by high concentrations of virus in the bloodstream.
- Viremia is identified as the presence of the virus within the blood, detectable via laboratory tests.

Although the dengue virus uses the immune system for replication and propagation, the body employs several defense mechanisms to counteract the infection:
- Infected cells produce and release interferons that inhibit viral replication and activate both the innate and adaptive immune responses.
- As the infection progresses, individuals often experience fever as a symptom.
The adaptive immune response includes:
- B cells, which generate antibodies such as IgM and IgG, that bind to and neutralize dengue viral particles, released into blood and lymph fluid.
- Cytotoxic T cells (also known as killer T cells or CD8+ T cells) that identify and lyse cells infected by the dengue virus.

When a person contracts the first dengue serotype infection:
- The dengue virus binds to FC receptors on the surface of host cells.
- The virus is internalized through receptor-mediated endocytosis, after which it replicates and releases new virions.
- As new viruses are released, B cell responses are induced, yielding antibodies while cytotoxic T cells act to eliminate infected cells.
- Antibodies generated from the first infection can opsonize the virus for enhanced recognition and destruction by macrophages.

Following recovery from an initial dengue infection, immunity to that serotype lasts for 2-3 months, but there is no long-term immunity against the other three serotypes.
Notably, in the 1960s, Dr. Scott Halstead observed increased risks of severe dengue in individuals with second infections compared to first-time cases.
- He proposed the concept of “antibody-dependent enhancement of infection” to explain the increased severity of a second infection.
Even though four dengue serotypes exist, memory immune cells only provide protection against the serotype that induced the first infection.
- In cases of second infections, antibodies from the first exposure may facilitate rather than inhibit the infection, worsening viremia.
This phenomenon can also affect infants who receive maternal antibodies that may enhance second serotype infections.

The antibodies from a first serotype do not bind effectively to the second serotype, which leads to poor neutralization of the virus.
- Loose binding allows the virus to escape apoptosis in macrophages, leading to replication within those cells, which then serve as hosts for the virus, distributing it to leukocyte organs and the bloodstream.
In contrast, subsequent infection with the same serotype does not result in enhanced disease due to pre-existing immunity.

A vaccine named Dengvaxia is available but has limitations in its effectiveness.
- It is recommended to be administered only to individuals previously infected with dengue.
- The manufacturer, Sanofi, invested over 1 billion dollars over more than 20 years to develop this vaccine.
- Dengvaxia is a live-attenuated tetravalent chimeric vaccine derived from yellow fever virus, genetically modified to express dengue virus proteins from serotypes 1, 2, 3, and 4.
This mixture is administered in a series of three doses, with intervals of six months between doses via subcutaneous injection.
Clinical studies indicate an effectiveness rate of 56 - 66% in preventing dengue in children, although it has been associated with severe outcomes in dengue-naive children who contract the virus post-vaccination.