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Pathophysiology

Similar to other filoviridae, EBOV replicates very efficiently in many cells, producing large amounts of virus in monocytes, macrophages, dendritic cells and other cells. Replication of the virus in monocytes triggers the release of high levels of inflammatory chemical signals.

Endothelial cells (cells lining the inside of blood vessels), macrophages, monocytes and liver cells are the main targets of infection. Macrophages are the first cells infected with the virus, and this infection results in cellular death. Endothelial cells may be infected within 3 days after exposure to the virus. The breakdown of endothelial cells leading to vascular injury can be attributed to EBOV glycoproteins. The widespread hemorrhage that occurs in affected people causes edema and hypovolemic shock. After infection, a secreted glycoprotein, small soluble glycoprotein (sGP) (or Ebola virus glycoprotein [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, a type of white blood cell, which enables the virus to evade the immune system by inhibiting early steps of neutrophil activation. These white blood cells also transport the virus within the entire body to tissues and organs such as the lymph nodes, liver, lungs and spleen.

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. The damage to human cells, caused by infection of the endothelial cells, decreases the integrity of blood vessels. This loss of vascular integrity increases with the synthesis of GP, which reduces the availability of specific integrins responsible for cell adhesion to the intercellular structure and causes damage to the liver, leading to improper clotting.

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, 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.[55] 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.