Editing Apoptosis (section)

===Viral infection===
Viral induction of apoptosis occurs when one or several cells of a living organism are<!--plural predicate to agree with "cells"--> infected with a [[virus]], leading to cell death. Cell death in organisms is necessary for the normal development of cells and the cell cycle maturation.<ref name=Indran>{{cite journal | vauthors = Indran IR, Tufo G, Pervaiz S, Brenner C | title = Recent advances in apoptosis, mitochondria and drug resistance in cancer cells | journal = Biochimica et Biophysica Acta (BBA) – Bioenergetics | volume = 1807 | issue = 6 | pages = 735–745 | date = June 2011 | pmid = 21453675 | doi = 10.1016/j.bbabio.2011.03.010 | doi-access = free }}</ref> It is also important in maintaining the regular functions and activities of cells.

Viruses can trigger apoptosis of infected cells via a range of mechanisms including:
* Receptor binding
* Activation of [[protein kinase R]] (PKR)
* Interaction with p53
* Expression of viral proteins coupled to MHC proteins on the surface of the infected cell, allowing recognition by cells of the immune system (such as [[Natural killer cell|natural killer]] and [[cytotoxic T cell]]s) that then induce the infected cell to undergo apoptosis.<ref name=Everett>{{cite journal | vauthors = Everett H, McFadden G | title = Apoptosis: an innate immune response to virus infection | journal = Trends in Microbiology | volume = 7 | issue = 4 | pages = 160–165 | date = April 1999 | pmid = 10217831 | doi = 10.1016/S0966-842X(99)01487-0 }}</ref>
[[Canine distemper virus]] (CDV) is known to cause apoptosis in central nervous system and lymphoid tissue of infected dogs in vivo and in vitro.<ref name=Nishi>{{cite journal | vauthors = Nishi T, Tsukiyama-Kohara K, Togashi K, Kohriyama N, Kai C | title = Involvement of apoptosis in syncytial cell death induced by canine distemper virus | journal = Comparative Immunology, Microbiology and Infectious Diseases | volume = 27 | issue = 6 | pages = 445–455 | date = November 2004 | pmid = 15325517 | doi = 10.1016/j.cimid.2004.01.007 }}</ref>
Apoptosis caused by CDV is typically induced via the [[death-inducing signaling complex|extrinsic pathway]], which activates [[caspases]] that disrupt cellular function and eventually leads to the cells death.<ref name=DelPuerto>{{cite journal | vauthors = Del Puerto HL, Martins AS, Milsted A, Souza-Fagundes EM, Braz GF, Hissa B, Andrade LO, Alves F, Rajão DS, Leite RC, Vasconcelos AC | display-authors = 6 | title = Canine distemper virus induces apoptosis in cervical tumor derived cell lines | journal = Virology Journal | volume = 8 | issue = 1 | pages = 334 | date = June 2011 | pmid = 21718481 | pmc = 3141686 | doi = 10.1186/1743-422X-8-334 | doi-access = free }}</ref> In normal cells, CDV activates caspase-8 first, which works as the initiator protein followed by the executioner protein caspase-3.<ref name=DelPuerto/>  However, apoptosis induced by CDV in HeLa cells does not involve the initiator protein caspase-8. HeLa cell apoptosis caused by CDV follows a different mechanism than that in vero cell lines.<ref name=DelPuerto/>  This change in the caspase cascade suggests CDV induces apoptosis via the [[intrinsic apoptosis|intrinsic pathway]], excluding the need for the initiator caspase-8. The executioner protein is instead activated by the internal stimuli caused by viral infection not a caspase cascade.<ref name=DelPuerto/>

The [[Oropouche virus]] (OROV) is found in the family ''[[Bunyaviridae]]''. The study of apoptosis brought on by ''Bunyaviridae'' was initiated in 1996, when it was observed that apoptosis was induced by the [[La Crosse encephalitis|La Crosse virus]] into the kidney cells of baby hamsters and into the brains of baby mice.<ref name=Acrani>{{cite journal | vauthors = Acrani GO, Gomes R, Proença-Módena JL, da Silva AF, Carminati PO, Silva ML, Santos RI, Arruda E | display-authors = 6 | title = Apoptosis induced by Oropouche virus infection in HeLa cells is dependent on virus protein expression | journal = Virus Research | volume = 149 | issue = 1 | pages = 56–63 | date = April 2010 | pmid = 20080135 | doi = 10.1016/j.virusres.2009.12.013 | doi-access = free }}</ref>

OROV is a disease that is transmitted between humans by the biting midge (''[[Culicoides paraensis]]'').<ref name=Azevedo>{{cite journal | vauthors = Azevedo RS, Nunes MR, Chiang JO, Bensabath G, Vasconcelos HB, Pinto AY, Martins LC, Monteiro HA, Rodrigues SG, Vasconcelos PF | display-authors = 6 | title = Reemergence of Oropouche fever, northern Brazil | journal = Emerging Infectious Diseases | volume = 13 | issue = 6 | pages = 912–915 | date = June 2007 | pmid = 17553235 | pmc = 2792853 | doi = 10.3201/eid1306.061114 }}</ref> It is referred to as a [[zoonotic]] [[arbovirus]] and causes febrile illness, characterized by the onset of a sudden fever known as Oropouche fever.<ref name=Santos>{{cite journal | vauthors = Santos RI, Rodrigues AH, Silva ML, Mortara RA, Rossi MA, Jamur MC, Oliver C, Arruda E | display-authors = 6 | title = Oropouche virus entry into HeLa cells involves clathrin and requires endosomal acidification | journal = Virus Research | volume = 138 | issue = 1–2 | pages = 139–143 | date = December 2008 | pmid = 18840482 | pmc = 7114418 | doi = 10.1016/j.virusres.2008.08.016 }}</ref>

The Oropouche virus also causes disruption in cultured cells – cells that are cultivated in distinct and specific conditions. An example of this can be seen in [[HeLa cells]], whereby the cells begin to degenerate shortly after they are infected.<ref name=Acrani/>

With the use of [[gel electrophoresis]], it can be observed that OROV causes [[DNA]] fragmentation in HeLa cells. It can be interpreted by counting, measuring, and analyzing the cells of the Sub/G1 cell population.<ref name=Acrani/> When HeLA cells are infected with OROV, the [[cytochrome C]] is released from the membrane of the mitochondria, into the cytosol of the cells. This type of interaction shows that apoptosis is activated via an intrinsic pathway.<ref name=Indran/>

In order for apoptosis to occur within OROV, viral uncoating, viral internalization, along with the replication of cells is necessary. Apoptosis in some viruses is activated by extracellular stimuli. However, studies have demonstrated that the OROV infection causes apoptosis to be activated through intracellular stimuli and involves the mitochondria.<ref name=Acrani/>

Many viruses encode proteins that can inhibit apoptosis.<ref name=Teodora>{{cite journal | vauthors = Teodoro JG, Branton PE | title = Regulation of apoptosis by viral gene products | journal = Journal of Virology | volume = 71 | issue = 3 | pages = 1739–1746 | date = March 1997 | pmid = 9032302 | pmc = 191242 | doi = 10.1128/jvi.71.3.1739-1746.1997 }}</ref> Several viruses encode viral homologs of Bcl-2. These homologs can inhibit proapoptotic proteins such as BAX and BAK, which are essential for the activation of apoptosis. Examples of viral Bcl-2 proteins include the [[Epstein-Barr virus]] BHRF1 protein and the [[adenovirus]] E1B 19K protein.<ref name=Polster>{{cite journal | vauthors = Polster BM, Pevsner J, Hardwick JM | title = Viral Bcl-2 homologs and their role in virus replication and associated diseases | journal = Biochimica et Biophysica Acta (BBA) – Molecular Cell Research | volume = 1644 | issue = 2–3 | pages = 211–227 | date = March 2004 | pmid = 14996505 | doi = 10.1016/j.bbamcr.2003.11.001 | doi-access =  }}</ref> Some viruses express caspase inhibitors that inhibit caspase activity and an example is the CrmA protein of cowpox viruses. Whilst a number of viruses can block the effects of TNF and Fas. For example, the M-T2 protein of myxoma viruses can bind TNF preventing it from binding the TNF receptor and inducing a response.<ref name=Hay>{{cite journal | vauthors = Hay S, Kannourakis G | title = A time to kill: viral manipulation of the cell death program | journal = The Journal of General Virology | volume = 83 | issue = Pt 7 | pages = 1547–1564 | date = July 2002 | pmid = 12075073 | doi = 10.1099/0022-1317-83-7-1547 | citeseerx = 10.1.1.322.6923 }}</ref> Furthermore, many viruses express p53 inhibitors that can bind p53 and inhibit its transcriptional transactivation activity. As a consequence, p53 cannot induce apoptosis, since it cannot induce the expression of proapoptotic proteins. The adenovirus E1B-55K protein and the [[hepatitis B virus]] HBx protein are examples of viral proteins that can perform such a function.<ref name=Wang>{{cite journal | vauthors = Wang XW, Gibson MK, Vermeulen W, Yeh H, Forrester K, Stürzbecher HW, Hoeijmakers JH, Harris CC | display-authors = 6 | title = Abrogation of p53-induced apoptosis by the hepatitis B virus X gene | journal = Cancer Research | volume = 55 | issue = 24 | pages = 6012–6016 | date = December 1995 | pmid = 8521383 }}</ref>

Viruses can remain intact from apoptosis in particular in the latter stages of infection. They can be exported in the ''apoptotic bodies'' that pinch off from the surface of the dying cell, and the fact that they are engulfed by phagocytes prevents the initiation of a host response. This favours the spread of the virus.<ref name="Hay"/> [[Prion]]s can cause apoptosis in [[neuron]]s.