Ebola

==Pathophysiology==
[[File:Ebola Pathenogensis path.svg|thumb|[[Pathogenesis]] schematic]]

Like other [[Filoviridae|filoviruses]], EBOV replicates very efficiently in many [[List of distinct cell types in the adult human body|cells]], producing large amounts of virus in [[monocyte]]s, [[macrophage]]s, [[dendritic cell]]s and other cells including [[hepatocyte|liver cells]], [[fibroblast]]s, and [[adrenal gland|adrenal gland cells]].<ref name="Ansari2014">{{Cite journal |vauthors=Ansari AA |date=September 2014 |title=Clinical features and pathobiology of Ebolavirus infection |journal=J Autoimmun |volume=55 |pages=1–9 |doi=10.1016/j.jaut.2014.09.001 |pmid=25260583}}</ref> Viral replication triggers [[cytokine storm|high levels of inflammatory chemical signals]] and leads to a [[Sepsis|septic state]].<ref name="Tosh2014">{{Cite journal |vauthors=Tosh PK, Sampathkumar P |date=December 2014 |title=What Clinicians Should Know About the 2014 Ebola Outbreak |journal=Mayo Clin Proc |volume=89 |issue=12 |pages=1710–17 |doi=10.1016/j.mayocp.2014.10.010 |pmid=25467644 |doi-access=free}}</ref>

EBOV is thought to infect humans through contact with mucous membranes or skin breaks.<ref name="Funk2014">{{Cite journal |vauthors=Funk DJ, Kumar A |date=November 2014 |title=Ebola virus disease: an update for anesthesiologists and intensivists |journal=Can J Anaesth |volume=62 |issue=1 |pages=80–91 |doi=10.1007/s12630-014-0257-z |pmc=4286619 |pmid=25373801}}</ref> After infection, [[endothelial cells]] (cells lining the inside of blood vessels), liver cells, and several types of immune cells such as [[Mononuclear phagocyte system|macrophages, monocytes]], and dendritic cells are the main targets of attack.<ref name="Funk2014" /> Following infection, immune cells carry the virus to nearby [[lymph node]]s where further reproduction of the virus takes place.<ref name="Funk2014" /> From there the virus can enter the bloodstream and [[lymphatic system]] and spread throughout the body.<ref name="Funk2014" /> Macrophages are the first cells infected with the virus, and this infection results in [[Apoptosis|programmed cell death]].<ref name="Chippaux2014" /> Other types of [[white blood cell]]s, such as [[lymphocyte]]s, also undergo programmed cell death leading to an abnormally [[lymphocytopenia|low concentration of lymphocytes]] in the blood.<ref name="Funk2014" /> This contributes to the weakened immune response seen in those infected with EBOV.<ref name="Funk2014" />

Endothelial cells may be infected within three days after exposure to the virus.<ref name="Chippaux2014" /> The breakdown of endothelial cells leading to [[blood vessel]] injury can be attributed to EBOV [[glycoprotein]]s. This damage occurs due to the synthesis of Ebola virus [[glycoprotein]] (GP), which reduces the availability of specific [[integrin]]s responsible for cell adhesion to the intercellular structure and causes liver damage, leading to [[coagulopathy|improper clotting]]. The widespread [[bleeding]] that occurs in affected people causes [[oedema|swelling]] and [[Hypovolemic shock|shock due to loss of blood volume]].<ref name="isbn0-7910-8505-8" /> The [[Disseminated intravascular coagulation|dysfunctional bleeding and clotting]] commonly seen in EVD has been attributed to increased activation of the [[Tissue factor pathway|extrinsic pathway]] of the [[coagulation cascade]] due to excessive [[tissue factor]] production by macrophages and monocytes.<ref name="Goeijenbier2014" />

After infection, a secreted [[glycoprotein]], small soluble glycoprotein (sGP or GP) is synthesised. EBOV replication overwhelms protein synthesis of infected cells and the host immune defences. The GP forms a [[Trimer (biochemistry)|trimeric complex]], which tethers the virus to the endothelial cells. The sGP forms a [[protein dimer|dimeric protein]] that interferes with the signalling of [[neutrophils]], another type of white blood cell. This enables the virus to evade the immune system by inhibiting early steps of neutrophil activation.{{medcn|date=August 2019}} Furthermore, the virus is capable of hijacking cellular metabolism. Studies have shown that Ebola virus-like particles can reprogram metabolism in both vascular and immune cells.<ref>{{cite journal | vauthors = Tang H, Abouleila Y, Saris A, Shimizu Y, Ottenhoff TH, Mashaghi A | title = Ebola virus-like particles reprogram cellular metabolism | journal = Journal of Molecular Medicine | volume = 101 | issue = 5 | pages = 557–568 | date = May 2023 | pmid = 36959259 | pmc = 10036248 | doi = 10.1007/s00109-023-02309-4 }}</ref> 

===Immune system evasion===
Filoviral infection also interferes with proper functioning of the [[innate immune system]].<ref name="Misasi2014" /><ref name="Olejnik2011">{{Cite journal |vauthors=Olejnik J, Ryabchikova E, Corley RB, Mühlberger E |date=August 2011 |title=Intracellular events and cell fate in filovirus infection |journal=Viruses |volume=3 |issue=8 |pages=1501–31 |doi=10.3390/v3081501 |pmc=3172725 |pmid=21927676 |doi-access=free}}</ref> 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]].<ref name="Kuhl2012" /><ref name="Ramanan2011">{{Cite journal |vauthors=Ramanan P, Shabman RS, Brown CS, Amarasinghe GK, Basler CF, Leung DW |date=September 2011 |title=Filoviral immune evasion mechanisms |journal=Viruses |volume=3 |issue=9 |pages=1634–49 |doi=10.3390/v3091634 |pmc=3187693 |pmid=21994800 |doi-access=free}}</ref>

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|Toll-like receptor 3 (TLR3)]], [[Toll-like receptor 7|TLR7]], [[Toll-like receptor 8|TLR8]] and [[Toll-like receptor 9|TLR9]]) recognise [[pathogen-associated molecular pattern|infectious molecules]] associated with the virus.<ref name="Kuhl2012" /> On TLR activation, proteins including [[Interferon Regulatory Factor 3|interferon regulatory factor 3]] and [[Interferon regulatory factor-7|interferon regulatory factor 7]] trigger a signalling cascade that leads to the expression of [[type 1 interferon]]s.<ref name="Kuhl2012" /> The type 1 interferons are then released and bind to the [[IFNAR1]] and [[IFNAR2]] receptors expressed on the surface of a neighbouring cell.<ref name="Kuhl2012" /> Once interferon has bound to its receptors on the neighbouring cell, the signalling proteins [[STAT1]] and [[STAT2]] are activated and move to the [[Cell nucleus|cell's nucleus]].<ref name="Kuhl2012" /> This triggers the expression of [[Interferome|interferon-stimulated genes]], which code for proteins with antiviral properties.<ref name="Kuhl2012" /> EBOV's V24 protein blocks the production of these antiviral proteins by preventing the STAT1 signalling protein in the neighbouring cell from entering the nucleus.<ref name="Kuhl2012" /> The VP35 protein directly inhibits the production of interferon-beta.<ref name="Ramanan2011" /> By inhibiting these immune responses, EBOV may quickly spread throughout the body.<ref name="Chippaux2014" />