{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T19:25:42Z","timestamp":1790105142160,"version":"4.0.1"},"reference-count":77,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2021,9,22]],"date-time":"2021-09-22T00:00:00Z","timestamp":1632268800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Scand J Immunol"],"published-print":{"date-parts":[[2021,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>During COVID\u201019 infection, reduced function of natural killer (NK) cells can lead to both compromised viral clearance and dysregulation of the immune response. Such dysregulation leads to overproduction of cytokines, a raised neutrophil\/lymphocyte ratio and monocytosis. This in turn increases IL\u20106 expression, which promotes scar and thrombus formation. Excess IL\u20106 also leads to a further reduction in NK function through downregulation of perforin expression, therefore forming a pathogenic auto\u2010inflammatory feedback loop. The perforin\/granzyme system of cytotoxicity is the main mechanism through which NK cells and cytotoxic T lymphocytes eliminate virally infected host cells, as well as being central to their role in regulating immune responses to microbial infection. Here, we present epidemiological evidence suggesting an association between perforin expression and resistance to COVID\u201019. In addition, we outline the manner in which a pathogenic auto\u2010inflammatory feedback loop could operate and the relationship of this loop to genes associated with severe COVID\u201019. Such an auto\u2010inflammatory loop may be amenable to synergistic multimodal therapy.<\/jats:p>","DOI":"10.1111\/sji.13102","type":"journal-article","created":{"date-parts":[[2021,9,12]],"date-time":"2021-09-12T18:07:40Z","timestamp":1631470060000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Perforin, COVID\u201019 and a possible pathogenic auto\u2010inflammatory feedback loop"],"prefix":"10.1111","volume":"94","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2009-3588","authenticated-orcid":false,"given":"Louise","family":"Cunningham","sequence":"first","affiliation":[{"name":"St. John\u2019s Institute of Dermatology Guy\u2019s and St Thomas\u2019 Hospital London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian","family":"Kimber","sequence":"additional","affiliation":[{"name":"Faculty of Biology Medicine and Health University of Manchester Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Basketter","sequence":"additional","affiliation":[{"name":"DABMEB Consultancy Ltd Wotton\u2010under\u2010Edge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Simmonds","sequence":"additional","affiliation":[{"name":"Nuffield Department of Medicine University of Oxford Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheila","family":"McSweeney","sequence":"additional","affiliation":[{"name":"St. John\u2019s Institute of Dermatology Guy\u2019s and St Thomas\u2019 Hospital London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christos","family":"Tziotzios","sequence":"additional","affiliation":[{"name":"St. John\u2019s Institute of Dermatology Guy\u2019s and St Thomas\u2019 Hospital London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John P.","family":"McFadden","sequence":"additional","affiliation":[{"name":"St. John\u2019s Institute of Dermatology Guy\u2019s and St Thomas\u2019 Hospital London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,9,22]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.02061"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1155\/2015\/281613"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/icb.2015.1"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri3839"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-12-324533"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.01869"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.m1091"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V92.7.2410"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1474-9726.2012.00839.x"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(20)30651-4"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2017.00255"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-020-0897-1"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-018-0251-7"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.00245"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.2337\/db13-1524"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/obr.13128"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1186\/1742-4933-4-3"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.atherosclerosis.2005.03.011"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.atherosclerosis.2012.02.009"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/cei.12210"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.01991"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1111\/imm.12421"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.3727\/000000005783982972"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-17-2460"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.26498"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2362.2010.02414.x"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-09-3292"},{"key":"e_1_2_6_29_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0257051"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.580237"},{"key":"e_1_2_6_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.26577"},{"key":"e_1_2_6_32_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.abd6832"},{"key":"e_1_2_6_33_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.166.10.6404"},{"key":"e_1_2_6_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41436-020-01077-7"},{"key":"e_1_2_6_35_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI138554"},{"key":"e_1_2_6_36_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2020.260307"},{"key":"e_1_2_6_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2020.110698"},{"key":"e_1_2_6_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2020.08.031"},{"key":"e_1_2_6_39_1","doi-asserted-by":"publisher","DOI":"10.1101\/2020.06.13.20127605"},{"key":"e_1_2_6_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41435-020-0098-4"},{"key":"e_1_2_6_41_1","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiv550"},{"key":"e_1_2_6_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41431-021-00886-x"},{"key":"e_1_2_6_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eclinm.2020.100630"},{"key":"e_1_2_6_44_1","doi-asserted-by":"publisher","DOI":"10.1002\/mgg3.344"},{"key":"e_1_2_6_45_1","doi-asserted-by":"publisher","DOI":"10.1136\/rmdopen-2020-001549"},{"key":"e_1_2_6_46_1","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.3HI0716-293RR"},{"key":"e_1_2_6_47_1","doi-asserted-by":"publisher","DOI":"10.1080\/2162402X.2017.1373234"},{"key":"e_1_2_6_48_1","doi-asserted-by":"publisher","DOI":"10.1111\/1523-1747.ep12292156"},{"key":"e_1_2_6_49_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-020-1051-9"},{"key":"e_1_2_6_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2020.106504"},{"key":"e_1_2_6_51_1","doi-asserted-by":"publisher","DOI":"10.1093\/nsr\/nwaa041"},{"key":"e_1_2_6_52_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2014.00508"},{"key":"e_1_2_6_53_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M308809200"},{"key":"e_1_2_6_54_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.02059"},{"key":"e_1_2_6_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2020.103026"},{"key":"e_1_2_6_56_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2513"},{"key":"e_1_2_6_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjcard.2003.12.054"},{"key":"e_1_2_6_58_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.jid.5700604"},{"key":"e_1_2_6_59_1","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.119.313137"},{"key":"e_1_2_6_60_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2011.01.007"},{"key":"e_1_2_6_61_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.39295"},{"key":"e_1_2_6_62_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-020-00557-9"},{"key":"e_1_2_6_63_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-03065-y"},{"key":"e_1_2_6_64_1","article-title":"Integrative analyses identify susceptibility genes underlying COVID\u201019 hospitalization","author":"Pathak GA","year":"2020","journal-title":"medRxiv"},{"key":"e_1_2_6_65_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2249.1999.01020.x"},{"key":"e_1_2_6_66_1","doi-asserted-by":"publisher","DOI":"10.1097\/00002030-200303070-00004"},{"key":"e_1_2_6_67_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2015-12-684399"},{"key":"e_1_2_6_68_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00395-013-0350-4"},{"key":"e_1_2_6_69_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0052027"},{"key":"e_1_2_6_70_1","doi-asserted-by":"publisher","DOI":"10.3390\/vaccines8040700"},{"key":"e_1_2_6_71_1","doi-asserted-by":"publisher","DOI":"10.1007\/PL00007458"},{"key":"e_1_2_6_72_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mehy.2020.109774"},{"key":"e_1_2_6_73_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)30628-0"},{"key":"e_1_2_6_74_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19124090"},{"key":"e_1_2_6_75_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2036.1996.22164025.x"},{"key":"e_1_2_6_76_1","doi-asserted-by":"publisher","DOI":"10.3109\/09546634.2013.806768"},{"key":"e_1_2_6_77_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2020.11.006"},{"key":"e_1_2_6_78_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(21)00676-0"}],"container-title":["Scandinavian Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/sji.13102","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/sji.13102","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/sji.13102","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,24]],"date-time":"2023-08-24T02:18:06Z","timestamp":1692843486000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/sji.13102"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,22]]},"references-count":77,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2021,11]]}},"alternative-id":["10.1111\/sji.13102"],"URL":"https:\/\/doi.org\/10.1111\/sji.13102","archive":["Portico"],"relation":{},"ISSN":["0300-9475","1365-3083"],"issn-type":[{"value":"0300-9475","type":"print"},{"value":"1365-3083","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,22]]},"assertion":[{"value":"2021-07-01","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-09-07","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-09-22","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e13102"}}