In this episode, Mast Cell releases a lot of histamine when she detects a harmless substance near the skin. Histamine splashes on the cells, making them wet and prone to electrical shocks while white blood cells are attracted to nothing. Mast Cell tries to defend herself from the angry comments of the other cells, but after being called “hysterical”, Mast Cell goes on a rampage, vowing never to do anything again. Afterwards, dengue virus is injected from a mosquito and infects Langerhans Cell and his co-workers, where they blow the other cells away. Mast Cell stops herself from releasing histamine, fearing she will only trouble the other cells. However, on Basophil’s urging, she releases histamine which attracts the white blood cells to kill the dengue virus-infected cells, saving the other cells.
In this blog post, I will touch on both the disease dengue fever and the chemical histamine. I will talk about the dengue virus and dengue fever. I will then describe what histamine does in the body before discussing whether mast cells play a good or bad role in dengue fever.
Describing the dengue virus
| Schematic | Microscopic | Anime |
 |  |  |
Dengue fever is a viral infection caused by the dengue virus, an enveloped, spherical virus of the Flavivirus genus in the Flaviviridae family. The virus is transmitted by female mosquitoes of the Aedes aegypti species, where they inject the virus into humans while feeding on blood. Dengue virus has four serotypes, each with one strand of ssRNA encoding 10 proteins. Three proteins are structural that assist in viral infection while seven non-structural (NS) proteins serve a variety of roles. For example, NS1 plays a role in severe dengue fever as it assists in replication of viral RNA when inside cells and stimulates inflammation when outside cells.
The structural proteins of the dengue virus play different roles in viral infection and replication inside cells. Cell infection by dengue virus starts when the E (envelope) protein, embedded in the dengue virus membrane, binds to receptors on cells. The virus is taken up inside cells into an endosome, where the viral and endosomal membranes fuse. This releases the viral RNA, which is coated in C (capsid) protein, into the cell. The viral RNA is eventually uncoated and used to generate new viral RNA strands and to produce viral proteins. The viral RNA and proteins are packaged in the rough endoplasmic reticulum of the cell. The packaged dengue virus travels to the cell membrane where it buds off from the infected cell. The M (membrane) protein embedded in the viral membrane assists in viral maturation and budding from infected cells.
Talking about dengue fever
Dengue fever is a viral infection that tends to be caught in the tropics, particularly in crowded urban areas. Dengue fever is becoming more common globally with the incidence of infection growing by more than 30-fold in recent years. Each year, 390 million people are afflicted with dengue fever. Of those infected, 96 million will exhibit symptoms, 500,000 will have severe dengue fever and 25,000 people will die. In addition, conservative estimates suggest that dengue fever costs the global economy US$8.9 billion/year. These figures are set to increase due to climate change enhancing the spread of Aedes aegypti mosquitoes which will increase the spread of the dengue virus.
People with dengue fever will typically exhibit fever, headache, vomiting, abdominal pain, diarrhoea and petechiae (small bruises). These symptoms appear due to the spread of the virus to different parts of the body which induces a systemic immune response. Dengue virus injected from a mosquito will typically infect white blood cells in the skin such as Langerhans cells. These infected white blood cells will migrate to the lymph node, where the virus will infect more white blood cells, allowing it to spread through the lymphatic system. Some dengue virus can also be injected into the bloodstream, where it can circulate around the body to infect a variety of cells. For example, dengue virus can infect and kill hepatocytes in the liver, impairing the liver’s function.
Most cases (90%) of dengue fever resolve within a week. However, dengue fever can worsen to dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS), where enough blood, plasma and fluids are lost from the bloodstream that blood pressure falls and the person goes into shock and potentially death. This is due to the presence of two pathological events: plasma leakage from the capillaries into tissue due to increased permeability of the capillary walls and bleeding due to low platelet counts that impair blood clotting. Dengue fever can also worsen via antibody-dependent enhancement (ADE), particularly when a person is infected with different dengue virus serotypes. This is where antibodies bind to the virus without neutralising the virus’ ability to infect cells. These virus-antibody complexes can be taken up by white blood cells to trigger strong immune and inflammatory responses that worsen dengue fever.
The actions of histamine in the human body
In the episode, Mast Cell was releasing histamine to trigger an immune response against harmful (dengue virus) and harmless (allergens) substances. Whilst it was an annoyance to Normal Cells as it made them wet and prone to electric shocks, it was also essential for attracting white blood cells to kill the dengue virus-infected cells. In real-life, what does histamine do in the body?
Histamine (2-(4-imidazolyl)-ethylamine) is an amine that produces a variety of actions in the human body, mainly dilating and increasing the permeability of the blood vessels. Histamine is produced by removing the carboxyl group (-COOH) in the amino acid histidine via histidine decarboxylase (HDC). HDC is found in a variety of cells such as neurons, parietal and gastric mucosal cells of the stomach and mast cells and basophils. In mast cells, histamine is stored in cytoplasmic granules. Upon mast cell activation by various stimuli such as allergens, drugs and chemicals, histamine is released. Histamine circulates around the body and acts on four histamine receptors (HRs) to exert different effects.
H1R
H1R is found in a variety of cells such as neurons, endothelial cells, smooth muscle cells and white blood cells such as monocytes, neutrophils and eosinophils. Depending on where H1R is expressed, this receptor exerts a variety of effects. H1R activation is associated with the symptoms of allergies and hay fever such as skin rashes and bronchoconstriction. H1R activation in the blood vessels increases vascular permeability by widening the gap between endothelial cells and dilates blood vessels by relaxing smooth muscle cells.
Did you know? H1R is also expressed in the brain, where its activation enhances alertness. This is why older generations of antihistamines that can enter the brain and block H1R can induce drowsiness as a side-effect.
H2R
H2R is also expressed in a variety of cells, not only white blood cells but also hepatocytes, endothelial cells, smooth muscle cells and parietal cells in the stomach. H2R opposes the actions of H1R, impeding immune responses and inflammation by suppressing the secretion of pro-inflammatory cytokines. In contrast, H2R activation relaxes smooth muscle cells similar to H1R, enabling the dilation of blood vessels and dilating bronchi. Lastly, H2R activation in parietal cells of the stomach stimulates the release of gastric acid which is required for breaking down food in the stomach.
H3R
H3R is found in the nervous system. H3R activation in the brain impairs the release of histamine and neurotransmitters such as acetylcholine, dopamine and GABA in the central and peripheral nervous systems.
H4R
H4R is expressed in a variety of cells in the small and large intestines, spleen, thymus, bone marrow and white blood cells. H4R activation releases white blood cells such as mast cells and eosinophils from the bone marrow and directs them to the inflamed site
The role of mast cells in dengue fever
Similar to the events of the episode, mast cells are indeed involved in the immune response to dengue fever. Mast cells are immediately activated upon detection of dengue virus when it is injected into the body. Activated mast cells will release mediators such as histamine, tryptase, chymase and VEGF and produce pro-inflammatory cytokines such as TNF-a, MCP-1 and RANTES. However, do mast cells play a beneficial or detrimental role in dengue fever? The answer: it depends on where histamine mediators are released.
If mast cell mediators are only released in the local area, mast cells can play a role in limiting the spread of and eliminating the virus. Mast cells are important in containing dengue virus infection as a deficiency of mast cells in mice was associated with an increased amount of virus in the draining lymph nodes, where it can potentially spread to other organs. This is because mast cell mediators are designed to attract white blood cells to the infected site to kill virally-infected cells, impeding viral replication. Mast cell mediators such as histamine can increase blood vessel permeability and activate endothelial cells. This enables white blood cells to roll and stick to the endothelium, allowing them to enter the infected site. In particular, NK and NKT cells are attracted to the infected site by mast cell mediators where they are able to kill virally-infected cells, eliminating the dengue virus.
However, if mast cell mediators are released into the bloodstream, they could contribute to the pathology of severe dengue fever by promoting plasma leakage into tissue. This is driven by increased concentrations of mast cell mediators such as histamine, tryptase, VEGF and chymase in the bloodstream which tend to be more common among patients with DHF and DSS compared to healthy controls and patients with mild dengue fever. The increased concentrations of mast cell mediators enhance the permeability of the endothelium, increasing plasma leakage into tissue. This reduces the volume of blood in the blood vessels, sending the person into shock characteristic of DSS and potentially death.
Using mast cell stabilisers that inhibit mast cell activation such as ketotifen have been shown to decrease the severity of dengue fever while preserving the immune system’s ability to detect and eliminate the virus. These drugs, which impede the release of mediators from dengue virus-infected cells, do this by reducing capillary permeability and plasma leakage, decreasing macrophage infiltration into inflamed sites and inhibiting systemic inflammation. These results highlight the possibility of using drugs to treat severe dengue fever in humans by inhibiting mast cell activity to prevent plasma loss and shock which could reduce the severity of infection.
Conclusion
Mast Cell played an important role in the episode in saving the Normal Cells from being blasted away by dengue virus-infected Langerhans Cells. Dengue virus, which are carried by mosquitoes, causes dengue fever and, if its replication is left uncontrolled, can worsen to DHF and DSS due to impaired blood clotting and increased plasma leakage into tissue. Mast cells can play both beneficial and detrimental roles in dengue fever depending on where mast cell mediators are released. While mast cell mediators such as histamine attract white blood cells to the infected site if released locally, they can also cause pathology in dengue fever if released systemically. Controlling the release of mast cell mediators could allow mast cells to control dengue fever instead of contributing to it.
In the next blog post, we will move to the stomach, where we will describe the pathogen that causes gastric ulcers. See you then!
References
I got most of my information on dengue fever from Guzman et al.’s primer on Dengue Infection in Nature Reviews Disease Primers. It covers many areas of dengue fever from its biology and its clinical effects in the human body to how it is treated. If you cannot access the primer, there is a free (albeit older) version of the review written by the same authors. Information on the effects of histamines in the human body were mostly gleaned from this website by the University of Bristol which goes into the functions of different histamine receptors in the human body.
There were a lot of disparate references to the link between mast cells and dengue fever in the scientific literature, and the research in this area is currently lacking. St. John et al.’s article from 2011 is the most notable study that looks at the link between mast cells and dengue fever. He also wrote a brief review detailing the potential beneficial and detrimental roles of mast cells in dengue fever which forms the basis for the paragraphs on this topic in this blog post.