Host Response to the Dengue Virus

Dengue viral infections can result in a range of symptoms. Some people show no symptoms or just have mild signs of the disease, but others develop severe complications. How does the body respond to a dengue infection? What factors put some people at greater risk of developing severe dengue illnesses than other people?

When a pathogen like the dengue virus invades the human body, how does the body defend itself? The body's main defense against any invading pathogen is the immune system, which is made up of two parts. The first part, called the innate immune system, provides the body with immediate and general protection from any invading pathogen. The innate immune response rapidly recognizes and responds to pathogens, but it does not provide a person with long-term immunity against an invading pathogen. The second part of the immune system, the adaptive immune system, produces cells that specifically and efficiently target the pathogen and infected cells. The cells produced by the adaptive immune system include antibody-secreting B cells and cytotoxic T cells. The antibodies (called immunoglobulin, or Ig) secreted by the B cells specifically recognize and bind to foreign molecules. The cytotoxic T cells kill cells that are infected with pathogens. The adaptive immune system takes longer to respond to an invading pathogen than the innate immune response, but it provides a person with long-term immunity against a pathogen.

What happens when the mosquito Aedes aegypti infects someone with the dengue virus? When an infected mosquito feeds on a person, it injects the dengue virus into the bloodstream. The virus infects nearby skin cells called keratinocytes, the most common cell type in the skin. The dengue virus also infects and replicates inside a specialized immune cell located in the skin, a type of dendritic cell called a Langerhans cell.

What are Langerhans cells? Langerhans cells detect invading pathogens and display molecules from the pathogens, called antigens, on their surface. The Langerhans cells then travel to the lymph nodes and alert the immune system to trigger the immune response because a pathogen is in the body. Lymph nodes are small organs located throughout the body connected by vessels that form a network called the lymphatic system. The lymph nodes are stations in the body for immune cells that help fight against infections.

Once the Langerhans cells are infected with the dengue virus, they travel from the infection site in the skin to the lymph nodes (Figure 1). How does the immune system respond? The infected Langerhans cells display dengue viral antigens on their surface, which activates the innate immune response by alerting two types of white blood cells, called monocytes and macrophages, to fight the virus. Normally, monocytes and macrophages ingest and destroy pathogens, but instead of destroying the dengue virus, both types of white blood cells are targeted and infected by the virus. The dengue virus tricks the immune system to get around its defenses and infect more cells. As the infected monocytes and macrophages travel through the lymphatic system, the dengue virus spreads throughout the body. During its journey, the dengue virus infects more cells, including those in the lymph nodes and bone marrow, macrophages in both the spleen and liver, and monocytes in the blood. The spread and increase of the virus results in viremia, a condition in which there is a high level of dengue virus in the bloodstream.

How can the body recover from a dengue infection? Although the dengue virus has tricked the immune system to infect cells and spread throughout the body, the immune system has additional defenses to fight the virus. The infected cells produce and release small proteins called interferons that are part of a large group of proteins called cytokines. Interferons have the ability to interfere with viral replication, and they activate both the innate and adaptive immune system defenses. They help the immune system recognize dengue-infected cells and help protect uninfected cells from infection. As the immune system fights the dengue infection, the person experiences a fever.

As the adaptive immune response starts fighting the dengue infection, B cells produce antibodies called IgM and IgG that are released in the blood and lymph fluid, where they specifically recognize and neutralize the dengue viral particles (Figure 2). In another adaptive immune response, cytotoxic T cells, or killer T cells, recognize and kill the cells that are infected with the dengue virus. The innate immune response activates the complement system, a response that helps the antibodies and white blood cells remove the virus. Together, the innate and adaptive immune responses neutralize the dengue infection, and the patient recovers from dengue fever.

After recovering from a first dengue infection, a person is protected from infection with the remaining three dengue serotypes for two to three months. Unfortunately, it is not long-term protection, and after that short period, a person can be infected with any of the remaining three dengue serotypes.

In the 1960s, Dr. Scott Halstead and his colleagues were studying the dengue virus in Thailand. They noticed that people who had been exposed to dengue a second time had an increased risk of severe dengue compared with those who had not been previously exposed. They wondered what makes a second dengue infection worse than the first.

Normally after an infection with a pathogen, the body "remembers" the infection for a long time because cells — called memory B cells and memory T cells — remain in the body. Because they remember the first infection, these memory cells can react rapidly to provide an adaptive response when an infection strikes a second time. Memory cells can remain in a person's body for many years, even an entire lifetime. Why, then, don't these memory cells help fight off a second dengue infection? Why is a second dengue infection often worse than the first infection?

Halstead proposed a phenomenon called "antibody-dependent enhancement of infection" to explain these observations. There are four different types of dengue viruses (serotypes), but the memory cells only provide immunity from reinfection with the dengue serotype that caused the first infection. When a person is infected with a second dengue serotype, Halstead proposed that antibodies from the first infection actually help spread the dengue viral infection and increase viremia, the amount of virus in the bloodstream. This phenomenon can also happen in children who received antibodies against dengue from their mothers while in the womb. Surprisingly, instead of destroying the virus, the existing antibodies and the antibodies newly produced by the memory B cells can actually help the virus infect host cells more efficiently (Figure 3). Ironically, the consequence of antibody-dependent enhancement is that the body's immune system response actually makes the clinical symptoms of dengue worse and raises the risk of severe dengue illnesses.

Researchers also observed that during a second infection with dengue, the cytotoxic T cells produced by the immune system provide only partial immunity against the new dengue serotype. The cytotoxic T cells do not effectively clear the virus from the body, and they release excess quantities of molecules called cytokines. In normal quantities, cytokines help the immune response; however, in high quantities, cytokines can produce serious inflammation and tissue damage such as leakage from the capillaries, possibly contributing to the development of severe dengue diseases.

Being exposed to dengue multiple times can increase the risk of severe dengue disease. What other factors might increase that risk? Certain chronic diseases — including asthma, sickle cell anemia, and diabetes mellitus — can increase a person's risk of developing a severe form of the disease. Variations in human leukocyte antigen alleles (a group of genes involved in immune system function) may also increase that risk. Although much is known about how the body responds to dengue infections, researchers are still trying to answer many questions about the disease.

The immune system is the body's primary defense against the dengue virus. When someone is infected with dengue, the innate and adaptive immune responses combine forces to fight the virus. B cells produce antibodies that specifically recognize and neutralize the foreign viral particles, and cytotoxic T cells recognize and kill cells that are infected with the dengue virus. People who are infected a subsequent time with a different type of the dengue virus may experience something called "antibody-dependent enhancement." This condition occurs when the immune response actually makes the clinical symptoms of dengue worse, increasing the risk of severe dengue.

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