December 04, 2017

Pathophysiology of Ebola Virus Disease

Ebola virus disease (EVD; formerly, Ebola haemorrhagic fever) is one of the Viral Hemorrhagic Fevers. It is a severe, often fatal disease in humans and nonhuman primates (such as monkeys, gorillas, and chimpanzees). It is one of the world’s deadliest and most virulent diseases.

EVD in humans is caused by four of five viruses of the genus Ebolavirus. The four are Bundibugyo virus (BDBV), Sudan virus (SUDV), Taï Forest virus (TAFV) and one simply called Ebola virus (EBOV, formerly Zaire Ebola virus). EBOV, species Zaire ebolavirus, is the most dangerous of the known EVD-causing viruses, and is responsible for the largest number of outbreaks. The fifth virus, Reston virus (RESTV), is not thought to cause disease in humans, but has caused disease in other primates. All five viruses are closely related to marburgviruses.


Similar to other filoviruses, EBOV replicates very efficiently in many cells, producing large amounts of virus in monocytes, macrophages, dendritic cells and other cells including liver cells, fibroblasts, and adrenal gland cells. Viral replication triggers the release of high levels of inflammatory chemical signals and leads to a septic state.

EBOV is thought to infect humans through contact with mucous membranes or through skin breaks. Once infected, endothelial cells (cells lining the inside of blood vessels), liver cells, and several types of immune cells such as macrophages, monocytes, and dendritic cells are the main targets of infection. Following infection with the virus, the immune cells carry the virus to nearby lymph nodes where further reproduction of the virus takes place. From there, the virus can enter the bloodstream and lymphatic system and spread throughout the body. Macrophages are the first cells infected with the virus, and this infection results in programmed cell death. Other types of white blood cells, such as lymphocytes, also undergo programmed cell death leading to an abnormally low concentration of lymphocytes in the blood. This contributes to the weakened immune response seen in those infected with EBOV.

Endothelial cells may be infected within three days after exposure to the virus. The breakdown of endothelial cells leading to blood vessel injury can be attributed to EBOV glycoproteins. This damage occurs due to the synthesis of Ebola virus glycoprotein (GP), which reduces the availability of specific integrins responsible for cell adhesion to the intercellular structure and causes liver damage, leading to improper clotting. The widespread bleeding that occurs in affected people causes swelling and shock due to loss of blood volume. The dysfunction in bleeding and clotting commonly seen in EVD has been attributed to increased activation of the extrinsic pathway of the coagulation cascade due to excessive tissue factor production by macrophages and monocytes.

After infection, a secreted glycoprotein, small soluble glycoprotein (sGP or GP) is synthesized. EBOV replication overwhelms protein synthesis of infected cells and the host immune defenses. The GP forms a trimeric complex, which tethers the virus to the endothelial cells. The sGP forms a dimeric protein that interferes with the signaling of neutrophils, another type of white blood cell, which enables the virus to evade the immune system by inhibiting early steps of neutrophil activation. The presence of viral particles and the cell damage resulting from viruses budding out of the cell causes the release of chemical signals (such as TNF-α, IL-6 and IL-8), which are molecular signals for fever and inflammation.

Pathophysiology of Ebola virus disease
Pathogenesis schematic (source: Wikipedia)

Immune system evasion

Filoviral infection also interferes with proper functioning of the innate immune system. EBOV proteins blunt the human immune system's response to viral infections by interfering with the cells' ability to produce and respond to interferon proteins such as interferon-alpha, interferon-beta, and interferon gamma.

The VP24 and VP35 structural proteins of EBOV play a key role in this interference. When a cell is infected with EBOV, receptors located in the cell's cytosol (such as RIG-I and MDA5) or outside of the cytosol (such as Toll-like receptor 3 (TLR3), TLR7, TLR8 and TLR9), recognize infectious molecules associated with the virus. On TLR activation, proteins including interferon regulatory factor 3 and interferon regulatory factor 7 trigger a signaling cascade that leads to the expression of type 1 interferons. The type 1 interferons are then released and bind to the IFNAR1 and IFNAR2 receptors expressed on the surface of a neighboring cell. Once interferon has bound to its receptors on the neighboring cell, the signaling proteins STAT1 and STAT2 are activated and move to the cell's nucleus. This triggers the expression of interferon-stimulated genes, which code for proteins with antiviral properties. EBOV's V24 protein blocks the production of these antiviral proteins by preventing the STAT1 signaling protein in the neighboring cell from entering the nucleus. The VP35 protein directly inhibits the production of interferon-beta. By inhibiting these immune responses, EBOV may quickly spread throughout the body.

Clinical features

Symptoms are non-specific making the disease difficult to diagnose. The symptoms can appear from 2 to 21 days after exposure. Many of those infected with the virus quickly get flu-like symptoms such as fever, intense weakness, muscle pain, headache and sore throat. This is followed by vomiting, diarrhoea, rash, impaired kidney and liver function, and in some cases, both internal and external bleeding. Severely ill patients require intensive supportive care.

For more, see What is Ebola Virus Disease?

Treatment and Vaccines

There is no specific vaccine or cure available for the disease. The most serious cases require intensive care and intravenous fluids to combat dehydration.

Sierra Leone Trial to Introduce a Vaccine against Ebola (STRIVE)
The College of Medicine and Allied Health Sciences (COMAHS), University of Sierra Leone, the Sierra Leone Ministry of Health and Sanitation (MoHS), and the U.S. Centers for Disease Control and Prevention (CDC) are working together on an Ebola vaccine clinical trial in Sierra Leone, which launched in April 2015.

This study, called the Sierra Leone Trial to Introduce a Vaccine against Ebola (STRIVE), is designed to assess the safety and efficacy of a candidate Ebola vaccine rVSV-ZEBOV among health and other frontline workers.

You can read more here and also on the CDC website.

Preventive measures

Ebola can be caught from both humans and animals. It spreads by direct contact with blood, body fluids or tissues of the infected.

Prevention involves decreasing the spread of the disease from infected monkeys and pigs to humans. This may be done by checking these animals for infection and killing and properly disposing of the bodies if the disease is discovered. Properly cooking meat and wearing protective clothing when handling meat may be helpful, as may wearing protective clothing and washing hands when around someone sick with the disease. Samples from people with the disease should be handled with an extra degree of caution.

Funeral rituals in which relatives and friends touch the body of the dead play an important role in transmission, as does handling dead (or living) animals carrying the virus. Touching these dead bodies must be avoided.

For current WHO recommendations on Prevention and Control, please see What Is Ebola Virus Disease?


Ebola Virus Disease is one of the world’s deadliest and most virulent diseases, with a case fatality rate of up to 90%. During an outbreak, those at higher risk of infection are health workers, family members and others in close contact with sick people and deceased patients.

Ebola virus disease outbreaks can devastate families and communities, but the infection can be controlled through the use of recommended protective measures in clinics and hospitals, at community gatherings, or at home.

1). WHO Global Alert and Response (GAR): Ebola virus disease (EVD). Accessed: 15.04.14. Available here: http://www.who.int/csr/disease/ebola/en/
2). Centers for Disease Control: 2014: Ebola Hemorrhagic Fever Outbreak in Guinea and Liberia. Accessed 15.04.14. Available here: http://www.cdc.gov/vhf/ebola/outbreaks/guinea/index.html
3). Wikipedia, the Free Encyclopedia: Ebola virus disease. Accessed 15.04.14. Available here: http://en.wikipedia.org/wiki/Ebola_virus_disease

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