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Non-cytolytic enterovirus
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== Non-cytolytic enterovirus may cause pathogenic effects leading to disease == In the cells it infects, non-cytolytic enterovirus synthesizes the full range of viral proteins, and these viral proteins may interfere with cellular function or cause pathology.<ref>{{Cite web|url=https://www.youtube.com/watch?v=3Ro7UlhSD-w&t=13m15s | title = How Does a Lytic Enterovirus Persist and Cause Chronic Disease? Enterovirus Session, International Symposium on Viruses in CFS & Post-viral Fatigue, Maryland, US, June 2008. Timecode: 13:15. | last=Chapman | first = Nora | date = 2008 | website = YouTube | archive-url=|archive-date=|url-status=|access-date=}}</ref> For example, enterovirus 2A protein, a protein produced by non-cytolytic enterovirus, has been shown in a murine model to generate dilated cardiomyopathy just on its own.<ref name="Xiong2007">{{Cite journal | last = Xiong | first = Dingding | last2 = Yajima | first2 = Toshitaka | last3 = Lim | first3 = Byung-Kwan | last4 = Stenbit | first4 = Antine | last5 = Dublin | first5 = Andrew | last6 = Dalton | first6 = Nancy D. | last7 = Summers-Torres | first7 = Daphne | last8 = Molkentin | first8 = Jeffery D. | last9 = Duplain | first9 = Herve | date = 2007-01-02 | title = Inducible cardiac-restricted expression of enteroviral protease 2A is sufficient to induce dilated cardiomyopathy|url=https://www.ncbi.nlm.nih.gov/pubmed/17190866|journal=Circulation|volume=115|issue=1 | pages = 94–102|doi=10.1161/CIRCULATIONAHA.106.631093|issn=1524-4539|pmid=17190866}}</ref> The 2A protein cleaves dystrophin, decreases the contractility of heart cardiomyocyte cells, as well as increasing cell membrane permeability; and 2A can promote virus spread to adjacent cells.<ref>{{Cite journal | last = Lévêque | first = Nicolas | last2 = Garcia | first2 = Magali | last3 = Bouin | first3 = Alexis | last4 = Nguyen | first4 = Joseph H.C. | last5 = Tran | first5 = Genevieve P. | last6 = Andreoletti | first6 = Laurent | last7 = Semler | first7 = Bert L. | date = 2017-08-15 | title = Functional Consequences of RNA 5'-Terminal Deletions on Coxsackievirus B3 RNA Replication and Ribonucleoprotein Complex Formation | url =https://www.ncbi.nlm.nih.gov/pubmed/28539455|journal=Journal of Virology|volume=91|issue=16|pages=|doi=10.1128/JVI.00423-17|issn=1098-5514|pmc=5533909|pmid=28539455|quote=Expression of 2A can cause significant impairment of cardiomyocyte function through proteolytic cleavage of dystrophin, resulting in a decrease in cell contractility, an increase in membrane permeability, and a focal spread of the virus to adjacent cells.|via=}}</ref> Enteroviral protein has been found in human heart tissues in dilated cardiomyopathy,<ref name="Zhang2000">{{Cite journal | last = Zhang | first = H. | last2 = Li | first2 = Y. | last3 = Peng | first3 = T. | last4 = Aasa | first4 = M. | last5 = Zhang | first5 = L. | last6 = Yang | first6 = Y. | last7 = Archard | first7 = L.C. | date = May 2000 | title = Localization of enteroviral antigen in myocardium and other tissues from patients with heart muscle disease by an improved immunohistochemical technique|url=https://www.ncbi.nlm.nih.gov/pubmed/10769041|journal=The Journal of Histochemistry and Cytochemistry: Official Journal of the Histochemistry Society|volume=48|issue=5 | pages = 579–584|doi=10.1177/002215540004800501|issn=0022-1554|pmid=10769041|rfc=|quote=enteroviral capsid protein VP1 was detected in duplicate myocardial tissue sections from six of nine myocarditis and three of four DCM cases.|via=}}</ref> as well as in the skeletal muscles, stomach and brain tissues of ME/CFS. In vitro studies indicate that non-cytolytic enteroviral RNA synthesizes similar amounts of viral protein as wild-type lytic enterovirus (though non-cytolytic viral RNA with the largest deletions generates less protein).<ref>{{Cite journal | last = Lévêque | first = Nicolas | last2 = Garcia | first2 = Magali | last3 = Bouin | first3 = Alexis | last4 = Nguyen | first4 = Joseph H.C. | last5 = Tran | first5 = Genevieve P. | last6 = Andreoletti | first6 = Laurent | last7 = Semler | first7 = Bert L. | date = 2017-07-27 | title = Functional Consequences of RNA 5′-Terminal Deletions on Coxsackievirus B3 RNA Replication and Ribonucleoprotein Complex Formation | url =https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5533909/|journal=Journal of Virology|volume=91|issue=16|pages=|doi=10.1128/JVI.00423-17|issn=0022-538X|pmc=5533909|pmid=28539455|quote=Overall, the data displayed in Fig. 4 show similar patterns of translation products for all RNAs tested, although the RNAs with the largest deletions (TD30 and TD49) produced lower overall levels of CVB3 proteins, particularly at the lower concentrations of RNA.|via=}}</ref> Furthermore, viral dsRNA is a potent inducer of type 1 interferons,<ref name="Chia2005-immuno">{{Cite journal | last = Chia | first = J.K.S. | date = Nov 2005 | title = The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/16254097/|journal=Journal of Clinical Pathology|volume=58|issue=11|pages=1126–1132|doi=10.1136/jcp.2004.020255|issn=0021-9746|pmc=1770761|pmid=16254097|quote=Among other immunostimulatory effects, double stranded RNA is a potent inducer of interferon synthesis, which activates intracellular RNase, with resultant degradation of excessive single stranded RNA. The finding of a higher level of RNase L activity in the mononuclear cells of patients with CFS is consistent with this paradigm.|via=}}</ref> so even the low levels of dsRNA found in non-cytolytic infections may be sufficient to chronically induce interferon, which might then lead to adverse effects (although it remains to be seen if these low levels are capable of stimulating type I interferon secretion,<ref>{{Cite journal | last = Lévêque | first = Nicolas | last2 = Garcia | first2 = Magali | last3 = Bouin | first3 = Alexis | last4 = Nguyen | first4 = Joseph H.C. | last5 = Tran | first5 = Genevieve P. | last6 = Andreoletti | first6 = Laurent | last7 = Semler | first7 = Bert L. | date = 2017-08-15 | title = Functional Consequences of RNA 5'-Terminal Deletions on Coxsackievirus B3 RNA Replication and Ribonucleoprotein Complex Formation | url =https://www.ncbi.nlm.nih.gov/pubmed/28539455|journal=Journal of Virology|volume=91|issue=16|pages=|doi=10.1128/JVI.00423-17|issn=1098-5514|pmc=5533909|pmid=28539455|quote=The synthesis of even low levels of double-stranded RNA by TD viruses could be sufficient to induce type I interferon (IFN) secretion by infected cardiomyocytes. ... It remains to be seen if innate immune sensors in cardiomyocytes can detect the very low levels of dsRNA synthesized by terminally deleted viruses and subsequently stimulate type I interferon secretion.|via=}}</ref> and one study suggests they may not, at least in murine heart muscle cells).<ref>{{Cite journal | last = Flynn | first = Claudia T. | last2 = Kimura | first2 = Taishi | last3 = Frimpong-Boateng | first3 = Kwesi | last4 = Harkins | first4 = Stephanie | last5 = Whitton | first5 = J. Lindsay | date = Dec 2017 | title = Immunological and pathological consequences of coxsackievirus RNA persistence in the heart|url=http://linkinghub.elsevier.com/retrieve/pii/S0042682217303264|journal=Virology|volume=512|pages=104–112|doi=10.1016/j.virol.2017.09.017|issn=0042-6822|pmc=5653433|pmid=28950225|quote=so we next used PCR arrays to evaluate the expression of host interferon-related mRNAs. No significant IFN signature was detected in RNA+ mice ... In summary, our data suggest that persistent cardiac CVB3 RNA does not cause a substantial ongoing innate response in the heart ... We therefore propose that the viral RNAs that remain at 30d p.i. most probably play no role in ongoing pathogenesis, and are merely the last remnants of the preceding infection.|via=}}</ref> Non-cytolytic enterovirus infection in the heart muscle in chronic CVB myocarditis and dilated cardiomyopathy has also been shown in some studies to induce autoantibodies which target mitochondria and thus substantially inhibit energy metabolism.<ref name="Schulze1999">{{Cite journal | last = Schulze | first = K. | last2 = Witzenbichler | first2 = B. | last3 = Christmann | first3 = C. | last4 = Schultheiss | first4 = H.P. | date = Oct 1999 | title = Disturbance of myocardial energy metabolism in experimental virus myocarditis by antibodies against the adenine nucleotide translocator |url =https://www.ncbi.nlm.nih.gov/pubmed/10615393|journal=Cardiovascular Research|volume=44|issue=1 | pages = 91–100|issn=0008-6363|pmid=10615393}}</ref><ref name="Schultheiss1996">{{Cite journal | last = Schultheiss | first = H. P. | last2 = Schulze | first2 = K. | last3 = Dörner | first3 = A. | date = Oct 1996 | title = Significance of the adenine nucleotide translocator in the pathogenesis of viral heart disease|url=https://www.ncbi.nlm.nih.gov/pubmed/8974071|journal=Molecular and Cellular Biochemistry|volume=|issue =163-164|pages=319–327|issn=0300-8177|pmid=8974071}}</ref><ref name="Schulze1995">{{Cite journal | last = Schulze | first = K. | last2 = Schultheiss | first2 = H.P. | date = Dec 1995 | title = The role of the ADP/ATP carrier in the pathogenesis of viral heart disease|url=https://www.ncbi.nlm.nih.gov/pubmed/8682105|journal=European Heart Journal|volume=16 | issue =Suppl O | pages = 64–67|issn=0195-668X|pmid=8682105}}</ref><ref name="Schultheiss1993">{{Cite journal | last = Schultheiss | first = H.P. | date = May 1993 | title = Disturbance of the myocardial energy metabolism in dilated cardiomyopathy due to autoimmunological mechanisms|url=https://www.ncbi.nlm.nih.gov/pubmed/8485833|journal=Circulation|volume=87|issue=5 Suppl|pages=IV43–48|issn=0009-7322|pmid=8485833}}</ref><ref name="Schulze1990">{{Cite journal | last = Schulze | first = K. | last2 = Becker | first2 = B.F. | last3 = Schauer | first3 = R. | last4 = Schultheiss | first4 = H.P. | date = Mar 1990 | title = Antibodies to ADP-ATP carrier--an autoantigen in myocarditis and dilated cardiomyopathy--impair cardiac function | url =https://www.ncbi.nlm.nih.gov/pubmed/2155073|journal=Circulation|volume=81|issue=3 | pages = 959–969|issn=0009-7322|pmid=2155073}}</ref> [https://forums.phoenixrising.me/index.php?threads/enterovirus-induced-ant-autoantibodies-the-cause-of-me-cfs.51145/ Article]
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