Editing Apoptosis (section)

==Implication in disease==

[[File:Apoptosis multi mouseliver.jpg|thumb|right|220px|A section of mouse liver showing several apoptotic cells, indicated by arrows]]
[[File:Apoptosis stained.jpg|thumb|right|220px|A section of mouse liver [[Staining (biology)|stained]] to show cells undergoing apoptosis (orange)]]
[[File:Apoptosis.jpg|thumb|right|220px|Neonatal cardiomyocytes ultrastructure after anoxia-reoxygenation]]

===Defective pathways===
The many different types of apoptotic pathways contain a multitude of different biochemical components, many of them not yet understood.<ref name="pathogenesis">{{cite journal | vauthors = Thompson CB | title = Apoptosis in the pathogenesis and treatment of disease | journal = Science | volume = 267 | issue = 5203 | pages = 1456–1462 | date = March 1995 | pmid = 7878464 | doi = 10.1126/science.7878464 | s2cid = 12991980 | bibcode = 1995Sci...267.1456T }}</ref> As a pathway is more or less sequential in nature, removing or modifying one component leads to an effect in another. In a living organism, this can have disastrous effects, often in the form of disease or disorder. A discussion of every disease caused by modification of the various apoptotic pathways would be impractical, but the concept overlying each one is the same: The normal functioning of the pathway has been disrupted in such a way as to impair the ability of the cell to undergo normal apoptosis. This results in a cell that lives past its "use-by date" and is able to replicate and pass on any faulty machinery to its progeny, increasing the likelihood of the cell's becoming cancerous or diseased.{{citation needed|date=November 2024}}

A recently described example of this concept in action can be seen in the development of a lung cancer called [[NCI-H460]].<ref name="h460">{{cite journal | vauthors = Yang L, Mashima T, Sato S, Mochizuki M, Sakamoto H, Yamori T, Oh-Hara T, Tsuruo T | display-authors = 6 | title = Predominant suppression of apoptosome by inhibitor of apoptosis protein in non-small cell lung cancer H460 cells: therapeutic effect of a novel polyarginine-conjugated Smac peptide | journal = Cancer Research | volume = 63 | issue = 4 | pages = 831–837 | date = February 2003 | pmid = 12591734 | url = http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=12591734 | access-date = 2008-09-04 | archive-date = 2012-12-20 | archive-url = https://archive.today/20121220182836/http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=12591734 | url-status = live }}</ref> The ''X-linked inhibitor of apoptosis protein'' ([[XIAP]]) is [[Gene expression|overexpressed]] in cells of the H460 [[cell line]]. XIAPs bind to the processed form of caspase-9 and suppress the activity of apoptotic activator [[cytochrome c]], therefore overexpression leads to a decrease in the number of proapoptotic agonists. As a consequence, the balance of anti-apoptotic and proapoptotic effectors is upset in favour of the former, and the damaged cells continue to replicate despite being directed to die. Defects in regulation of apoptosis in cancer cells occur often at the level of control of transcription factors. As a particular example, defects in molecules that control transcription factor NF-κB in cancer change the mode of transcriptional regulation and the response to apoptotic signals, to curtail dependence on the tissue that the cell belongs. This degree of independence from external survival signals, can enable cancer metastasis.<ref>{{cite journal | vauthors = Vlahopoulos SA | title = Aberrant control of NF-κB in cancer permits transcriptional and phenotypic plasticity, to curtail dependence on host tissue: molecular mode | journal = Cancer Biology & Medicine | volume = 14 | issue = 3 | pages = 254–270 | date = August 2017 | pmid = 28884042 | pmc = 5570602 | doi = 10.20892/j.issn.2095-3941.2017.0029 }}</ref>

====Dysregulation of p53====
The tumor-suppressor protein [[p53]] accumulates when DNA is damaged due to a chain of biochemical factors. Part of this pathway includes alpha-[[interferon]] and beta-interferon, which induce transcription of the ''p53'' gene, resulting in the increase of p53 protein level and enhancement of cancer cell-apoptosis.<ref name="takaoka">{{cite journal | vauthors = Takaoka A, Hayakawa S, Yanai H, Stoiber D, Negishi H, Kikuchi H, Sasaki S, Imai K, Shibue T, Honda K, Taniguchi T | display-authors = 6 | title = Integration of interferon-alpha/beta signalling to p53 responses in tumour suppression and antiviral defence | journal = Nature | volume = 424 | issue = 6948 | pages = 516–523 | date = July 2003 | pmid = 12872134 | doi = 10.1038/nature01850 | doi-access = free | bibcode = 2003Natur.424..516T }}</ref> p53 prevents the cell from replicating by stopping the [[cell cycle]] at G1, or interphase, to give the cell time to repair; however, it will induce apoptosis if damage is extensive and repair efforts fail.<ref name="pmid12052432">{{cite journal | vauthors = Bernstein C, Bernstein H, Payne CM, Garewal H | title = DNA repair/pro-apoptotic dual-role proteins in five major DNA repair pathways: fail-safe protection against carcinogenesis | journal = Mutation Research | volume = 511 | issue = 2 | pages = 145–178 | date = June 2002 | pmid = 12052432 | doi = 10.1016/S1383-5742(02)00009-1 | bibcode = 2002MRRMR.511..145B }}</ref> Any disruption to the regulation of the ''p53'' or interferon genes will result in impaired apoptosis and the possible formation of tumors.<ref>{{Cite journal |last=Soussi |first=Thierry |date=2000 |title=The p53 Tumor Suppressor Gene: From Molecular Biology to Clinical Investigation |url=https://nyaspubs.onlinelibrary.wiley.com/doi/10.1111/j.1749-6632.2000.tb06705.x |journal=Annals of the New York Academy of Sciences |language=en |volume=910 |issue=1 |pages=121–139 |doi=10.1111/j.1749-6632.2000.tb06705.x |pmid=10911910 |bibcode=2000NYASA.910..121S |issn=1749-6632}}</ref>

===Inhibition===
Inhibition of apoptosis can result in a number of cancers, inflammatory diseases, and viral infections. It was originally believed that the associated accumulation of cells was due to an increase in cellular proliferation, but it is now known that it is also due to a decrease in cell death. The most common of these diseases is cancer, the disease of excessive cellular proliferation, which is often characterized by an overexpression of [[inhibitor of apoptosis|IAP]] family members. As a result, the malignant cells experience an abnormal response to apoptosis induction: Cycle-regulating genes (such as p53, ras or c-myc) are mutated or inactivated in diseased cells, and further genes (such as bcl-2) also modify their expression in tumors. Some apoptotic factors are vital during mitochondrial respiration e.g. cytochrome C.<ref name="iopscience.iop.org">{{cite journal | vauthors = Kaczanowski S | title = Apoptosis: its origin, history, maintenance and the medical implications for cancer and aging | journal = Physical Biology | volume = 13 | issue = 3 | pages = 031001 | date = May 2016 | pmid = 27172135 | doi = 10.1088/1478-3975/13/3/031001 | url = http://eprints.ibb.waw.pl/1615/1/Apoptosis2016.pdf | access-date = 2019-12-26 | url-status = dead | bibcode = 2016PhBio..13c1001K | s2cid = 5549982 | archive-url = https://web.archive.org/web/20190428231913/http://eprints.ibb.waw.pl/1615/1/Apoptosis2016.pdf | archive-date = 2019-04-28 }}</ref> Pathological inactivation of apoptosis in cancer cells is correlated with frequent respiratory metabolic shifts toward glycolysis (an observation known as the "Warburg hypothesis".<ref name="Warburg_1956">{{cite journal | vauthors = Warburg O | title = On the origin of cancer cells | journal = Science | volume = 123 | issue = 3191 | pages = 309–314 | date = February 1956 | pmid = 13298683 | doi = 10.1126/science.123.3191.309 | bibcode = 1956Sci...123..309W }}</ref>

====HeLa cell====
Apoptosis in [[HeLa]]{{efn|HeLa cells are an immortalized cancer cell line used frequently in research. The cell line was established by removing cells directly from [[Henrietta Lacks]], a cancer patient.}} cells is inhibited by proteins produced by the cell; these inhibitory proteins target retinoblastoma tumor-suppressing proteins.<ref name=DelPuerto/> These tumor-suppressing proteins regulate the cell cycle, but are rendered inactive when bound to an inhibitory protein.<ref name=DelPuerto/> HPV E6 and E7 are inhibitory proteins expressed by the human papillomavirus, HPV being responsible for the formation of the cervical tumor from which HeLa cells are derived.<ref name=Liu>{{cite journal | vauthors = Liu HC, Chen GG, Vlantis AC, Tse GM, Chan AT, van Hasselt CA | title = Inhibition of apoptosis in human laryngeal cancer cells by E6 and E7 oncoproteins of human papillomavirus 16 | journal = Journal of Cellular Biochemistry | volume = 103 | issue = 4 | pages = 1125–1143 | date = March 2008 | pmid = 17668439 | doi = 10.1002/jcb.21490 | s2cid = 1651475 }}</ref> HPV E6 causes p53, which regulates the cell cycle, to become inactive.<ref name=Niu>{{cite journal | vauthors = Niu XY, Peng ZL, Duan WQ, Wang H, Wang P | title = Inhibition of HPV 16 E6 oncogene expression by RNA interference in vitro and in vivo | journal = International Journal of Gynecological Cancer | volume = 16 | issue = 2 | pages = 743–751 | year = 2006 | pmid = 16681755 | doi = 10.1111/j.1525-1438.2006.00384.x | doi-broken-date = 27 March 2025 }}</ref> HPV E7 binds to retinoblastoma tumor suppressing proteins and limits its ability to control cell division.<ref name=Niu/>  These two inhibitory proteins are partially responsible for HeLa cells' immortality by inhibiting apoptosis to occur.<ref name="Liu McKalip">{{cite journal | vauthors = Liu Y, McKalip A, Herman B | title = Human papillomavirus type 16 E6 and HPV-16 E6/E7 sensitize human keratinocytes to apoptosis induced by chemotherapeutic agents: roles of p53 and caspase activation | journal = Journal of Cellular Biochemistry | volume = 78 | issue = 2 | pages = 334–349 | date = May 2000 | pmid = 10842327 | doi = 10.1002/(sici)1097-4644(20000801)78:2<334::aid-jcb15>3.3.co;2-6 }}</ref>

====Treatments====
{{Further|topic=a clinical pathology test that measures apoptosis|MiCK assay}}
The main method of treatment for potential death from signaling-related diseases involves either increasing or decreasing the susceptibility of apoptosis in diseased cells, depending on whether the disease is caused by either the inhibition of or excess apoptosis. For instance, treatments aim to restore apoptosis to treat diseases with deficient cell death and to increase the apoptotic threshold to treat diseases involved with excessive cell death. To stimulate apoptosis, one can increase the number of death receptor ligands (such as TNF or TRAIL), antagonize the anti-apoptotic Bcl-2 pathway, or introduce Smac mimetics to inhibit the inhibitor (IAPs).<ref name="pmid31380246">{{cite journal | vauthors = Jan R, Chaudhry GE | title = Understanding Apoptosis and Apoptotic Pathways Targeted Cancer Therapeutics | journal = Advanced Pharmaceutical Bulletin | volume = 9 | issue = 2 | pages = 205–218 | date = June 2019 | pmid = 31380246 | pmc = 6664112 | doi = 10.15171/apb.2019.024 }}</ref> The addition of agents such as Herceptin, Iressa, or Gleevec works to stop cells from cycling and causes apoptosis activation by blocking growth and survival signaling further upstream. Finally, adding p53-[[MDM2]] complexes displaces p53 and activates the p53 pathway, leading to cell cycle arrest and apoptosis. Many different methods can be used either to stimulate or to inhibit apoptosis in various places along the death signaling pathway.<ref>{{cite journal | vauthors = Boehm I | title = Apoptosis in physiological and pathological skin: implications for therapy | journal = Current Molecular Medicine | volume = 6 | issue = 4 | pages = 375–394 | date = June 2006 | pmid = 16900661 | doi = 10.2174/156652406777435390 }}</ref>

Apoptosis is a multi-step, multi-pathway cell-death programme that is inherent in every cell of the body. In cancer, the apoptosis cell-division ratio is altered. Cancer treatment by chemotherapy and irradiation kills target cells primarily by inducing apoptosis.<ref>{{cite journal |last1=Lowe |first1=Scott W. |last2=Lin |first2=Albert W. |title=Apoptosis in cancer |journal=Carcinogenesis |date=2000-03-01 |volume=21 |issue=3 |pages=485–495 |doi=10.1093/carcin/21.3.485 |pmid=10688869 |url=https://www.nature.com/articles/4401986 |access-date=2025-01-22}}</ref>

===Hyperactive apoptosis===
On the other hand, loss of control of cell death (resulting in excess apoptosis) can lead to neurodegenerative diseases, hematologic diseases, and tissue damage. Neurons that rely on mitochondrial respiration undergo apoptosis in neurodegenerative diseases such as Alzheimer's<ref name="pmid7704018">{{cite journal | vauthors = LaFerla FM, Tinkle BT, Bieberich CJ, Haudenschild CC, Jay G | title = The Alzheimer's A beta peptide induces neurodegeneration and apoptotic cell death in transgenic mice | journal = Nature Genetics | volume = 9 | issue = 1 | pages = 21–30 | date = January 1995 | pmid = 7704018 | doi = 10.1038/ng0195-21 | s2cid = 20016461 }}</ref> and Parkinson's.<ref name="pmid8782165">{{cite journal | vauthors = Mochizuki H, Goto K, Mori H, Mizuno Y | title = Histochemical detection of apoptosis in Parkinson's disease | journal = Journal of the Neurological Sciences | volume = 137 | issue = 2 | pages = 120–123 | date = May 1996 | pmid = 8782165 | doi = 10.1016/0022-510X(95)00336-Z | s2cid = 44329454 }}</ref> (an observation known as the "Inverse Warburg hypothesis"<ref name="iopscience.iop.org"/><ref name="pmid25642192">{{cite journal | vauthors = Demetrius LA, Magistretti PJ, Pellerin L | title = Alzheimer's disease: the amyloid hypothesis and the Inverse Warburg effect | journal = Frontiers in Physiology | volume = 5 | pages = 522 | date = 2014 | pmid = 25642192 | pmc = 4294122 | doi = 10.3389/fphys.2014.00522 | doi-access = free }}</ref>). Moreover, there is an inverse epidemiological comorbidity between neurodegenerative diseases and cancer.<ref name="pmid23843468">{{cite journal | vauthors = Musicco M, Adorni F, Di Santo S, Prinelli F, Pettenati C, Caltagirone C, Palmer K, Russo A | display-authors = 6 | title = Inverse occurrence of cancer and Alzheimer disease: a population-based incidence study | journal = Neurology | volume = 81 | issue = 4 | pages = 322–328 | date = July 2013 | pmid = 23843468 | doi = 10.1212/WNL.0b013e31829c5ec1 | s2cid = 22792702 }}</ref> The progression of HIV is directly linked to excess, unregulated apoptosis.  In a healthy individual, the number of CD4+ lymphocytes is in balance with the cells generated by the bone marrow; however, in HIV-positive patients, this balance is lost due to an inability of the bone marrow to regenerate CD4+ cells.  In the case of HIV, CD4+ lymphocytes die at an accelerated rate through uncontrolled apoptosis, when stimulated.
At the molecular level, hyperactive apoptosis can be caused by defects in signaling pathways that regulate the Bcl-2 family proteins. Increased expression of apoptotic proteins such as BIM, or their decreased proteolysis, leads to cell death and can cause a number of pathologies, depending on the cells where excessive activity of BIM occurs. Cancer cells can escape apoptosis through mechanisms that suppress BIM expression or by increased proteolysis of BIM.{{Citation needed|date=December 2019|reason=removed citation to predatory publisher content}}

====Treatments====
Treatments aiming to inhibit works to block specific caspases. Finally, the Akt protein kinase promotes cell survival through two pathways. Akt phosphorylates and inhibits Bad (a Bcl-2 family member), causing Bad to interact with the [[14-3-3]] scaffold, resulting in Bcl dissociation and thus cell survival. Akt also activates IKKα, which leads to NF-κB activation and cell survival. Active NF-κB induces the expression of anti-apoptotic genes such as Bcl-2, resulting in inhibition of apoptosis. NF-κB has been found to play both an antiapoptotic role and a proapoptotic role depending on the stimuli utilized and the cell type.<ref name="Farhana_2005">{{cite journal | vauthors = Farhana L, Dawson MI, Fontana JA | title = Apoptosis induction by a novel retinoid-related molecule requires nuclear factor-kappaB activation | journal = Cancer Research | volume = 65 | issue = 11 | pages = 4909–4917 | date = June 2005 | pmid = 15930313 | doi = 10.1158/0008-5472.CAN-04-4124 | doi-access =  }}</ref>

===HIV progression===
The progression of the [[human immunodeficiency virus]] infection into [[AIDS]] is due primarily to the depletion of [[T helper cell|CD4+ T-helper lymphocytes]] in a manner that is too rapid for the body's bone marrow to replenish the cells, leading to a compromised immune system. One of the mechanisms by which T-helper cells are depleted is apoptosis, which results from a series of biochemical pathways:<ref name="Judie">{{cite journal | vauthors = Alimonti JB, Ball TB, Fowke KR | title = Mechanisms of CD4+ T lymphocyte cell death in human immunodeficiency virus infection and AIDS | journal = The Journal of General Virology | volume = 84 | issue = Pt 7 | pages = 1649–1661 | date = July 2003 | pmid = 12810858 | doi = 10.1099/vir.0.19110-0 | doi-access = free }}</ref>
# HIV enzymes deactivate anti-apoptotic ''Bcl-2''. This does not directly cause cell death but primes the cell for apoptosis should the appropriate signal be received.  In parallel, these enzymes activate proapoptotic ''procaspase-8'', which does directly activate the mitochondrial events of apoptosis.
# HIV may increase the level of cellular proteins that prompt Fas-mediated apoptosis.
# HIV proteins decrease the amount of [[CD4]] glycoprotein marker present on the cell membrane.
# Released viral particles and proteins present in extracellular fluid are able to induce apoptosis in nearby "bystander" T helper cells.
# HIV decreases the production of molecules involved in marking the cell for apoptosis, giving the virus time to replicate and continue releasing apoptotic agents and virions into the surrounding tissue.
# The infected CD4+ cell may also receive the death signal from a cytotoxic T cell.

Cells may also die as direct consequences of viral infections. HIV-1 expression induces tubular cell G2/M arrest and apoptosis.<ref>{{cite journal | vauthors = Vashistha H, Husain M, Kumar D, Yadav A, Arora S, Singhal PC | title = HIV-1 expression induces tubular cell G2/M arrest and apoptosis | journal = Renal Failure | volume = 30 | issue = 6 | pages = 655–664 | year = 2008 | pmid = 18661417 | doi = 10.1080/08860220802134672 | s2cid = 25787186 | doi-access =  }}</ref>  The progression from HIV to AIDS is not immediate or even necessarily rapid; HIV's cytotoxic activity toward CD4+ lymphocytes is classified as AIDS once a given patient's CD4+ cell count falls below 200.<ref>{{cite web |author=Indiana University Health |url=http://iuhealth.org/riley/infectious-diseases/hiv/aids-defining-criteria/ |title=AIDS Defining Criteria &#124; Riley |publisher=IU Health |access-date=2013-01-20 |archive-url=https://web.archive.org/web/20130526052627/http://iuhealth.org/riley/infectious-diseases/hiv/aids-defining-criteria/ |archive-date=2013-05-26 |url-status=dead }}</ref>

Researchers from Kumamoto University in Japan have developed a new method to eradicate HIV in viral reservoir cells, named "Lock-in and apoptosis." Using the synthesized compound Heptanoylphosphatidyl L-Inositol Pentakisphophate (or L-Hippo) to bind strongly to the HIV protein PR55Gag, they were able to suppress viral budding. By suppressing viral budding, the researchers were able to trap the HIV virus in the cell and allow for the cell to undergo apoptosis (natural cell death). Associate Professor Mikako Fujita has stated that the approach is not yet available to HIV patients because the research team has to conduct further research on combining the drug therapy that currently exists with this "Lock-in and apoptosis" approach to lead to complete recovery from HIV.<ref>{{cite journal | vauthors = Tateishi H, Monde K, Anraku K, Koga R, Hayashi Y, Ciftci HI, DeMirci H, Higashi T, Motoyama K, Arima H, Otsuka M, Fujita M | display-authors = 6 | title = A clue to unprecedented strategy to HIV eradication: "Lock-in and apoptosis" | journal = Scientific Reports | volume = 7 | issue = 1 | pages = 8957 | date = August 2017 | pmid = 28827668 | pmc = 5567282 | doi = 10.1038/s41598-017-09129-w | bibcode = 2017NatSR...7.8957T }}</ref>

===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.