Pathophysiology

Pathogenesis schematic

Cells lining the inside of blood vessels (endothelial cells), macrophages, monocytes, and liver cells are the main targets of infection. Macrophages are the first cells to be infected with the virus and this infection results in cellular death. Endothelial cells can be infected within three days after exposure to the virus. After infection, a secreted glycoprotein, known as small soluble glycoprotein (sGP) or as the Ebola virus glycoprotein (GP), is synthesized. Ebolavirus replication overwhelms protein synthesis of infected cells and host immune defenses. The GP forms a trimeric complex, which binds 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 allows the virus to evade the immune system by inhibiting early steps of neutrophil activation. These white blood cells also serve as carriers to transport the virus throughout the entire body to places such as the lymph nodes, liver, lungs, and spleen. The presence of viral particles and 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 blood vessel integrity. This loss of vascular integrity is furthered with the synthesis of GP, which reduces specific integrins responsible for cell adhesion to the intercellular structure, and damage to the liver, which leads to improper clotting.

Filoviral infection is also known to interfere with proper functioning of the innate immune system. Ebolavirus proteins blunt the human immune system's response to viral infections by interfering with cells' ability to produce and respond to interferon proteins such as interferon-alpha, interferon-beta, and interferon gamma. This interference is accomplished by the VP24 and VP35 ebolavirus structural proteins. When a cell is infected with ebolavirus, receptors located in the cell's cytosol (such as RIG-I and MDA5) or outside of the cytosol (such as Toll-like receptor 3, Toll-like receptor 7, Toll-like receptor 8, and Toll-like receptor 9), recognize infectious molecules associated with the virus. After these receptors are activated, proteins including interferon regulatory factor 3 and interferon regulatory factor 7 start a signaling cascade that leads to the expression of type 1 interferons. Type 1 interferons are then released and bind to the IFNAR1 and IFNAR2 receptors expressed on the surface of the 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 that have antiviral properties. Ebolavirus' V24 protein prevents the STAT1 signaling protein in the neighboring cell from entering the nucleus and therefore prevents the creation of these antiviral proteins. A separate ebolavirus protein, known as VP35, directly inhibits the production of interferon-beta. The ability to inhibit these immune responses creates an environment in which Ebolavirus can quickly spread throughout the body.

sources : wikipedia