{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T08:20:15Z","timestamp":1788337215379,"version":"build-2803163510"},"reference-count":68,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2025,7,11]],"date-time":"2025-07-11T00:00:00Z","timestamp":1752192000000},"content-version":"vor","delay-in-days":10,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Immunity Inflam &amp;amp; Disease"],"published-print":{"date-parts":[[2025,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Aim<\/jats:title><jats:p>Acute rheumatic fever (ARF) and Rheumatic heart disease (RHD) are autoimmune sequalae, that develops in a proportion of individuals exposed to group A streptococcal infection. The autoimmune pathology of ARF\/RHD is multifactorial. Both host and pathogen\u2010associated factors including genetic predisposition, inflammatory responses, tissue cross\u2010reactive antibodies and T\u2010cells contribute to disease development and progression. Hitherto, the role of inflammatory responses in ARF\/RHD has never been demonstrated in animal models. In this study for the first time, using the Rat Autoimmune valvulitis model of RHD, we demonstrate the requirement for inflammatory responses in promoting cardiac damage in ARF\/RHD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>To determine the role of inflammatory responses we used <jats:italic>Bordetella pertussis<\/jats:italic> toxin (BPTx) as an adjuvant to enhance the inflammatory responses initiated by GAS M protein.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Lewis rats injected with GAS rM5 emulsified in Complete Freund's Adjuvant (CFA) and co\u2010adjuvant BPTx, had enhanced valvulitis and inflammatory changes as shown by; (a) elevated levels of circulating inflammatory cytokines; (b) functional changes characterized by a prolonged P\u2010R interval in electrocardiography, (c) enhanced cross\u2010reactive antibody production against cardiac and connective tissue proteins; and (d) increased infiltration of IFN\u2010\u03b3+ and IL\u201017A+ secreting leukocytes into myocardium and valvular tissues.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These studies have established that in addition to exposure to GAS M protein, BPTx accelerate the inflammatory and autoimmune processes leading to cardiac damage. These observations substantiate the hypothesis that, in susceptible individuals robust inflammatory responses facilitate the progression of ARF\/RHD.<\/jats:p><\/jats:sec>","DOI":"10.1002\/iid3.70221","type":"journal-article","created":{"date-parts":[[2025,7,11]],"date-time":"2025-07-11T10:39:56Z","timestamp":1752230396000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Inflammatory Responses Potentiate GAS M Protein Induced Cardiac Damage in an Experimental Model of Rheumatic Heart Disease"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7190-9666","authenticated-orcid":false,"given":"Rukshan A. M.","family":"Rafeek","sequence":"first","affiliation":[{"name":"School of Science &amp; Technology University of New England Armidale New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone L.","family":"Reynolds","sequence":"additional","affiliation":[{"name":"Institute for Biomedicine and Glycomics Griffith University Brisbane Queensland Australia"},{"name":"QIMR Berghofer Medical Research Institute Brisbane Queensland Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manisha","family":"Pandey","sequence":"additional","affiliation":[{"name":"Institute for Biomedicine and Glycomics Griffith University Brisbane Queensland Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"McMillan","sequence":"additional","affiliation":[{"name":"School of Science &amp; Technology University of New England Armidale New South Wales Australia"},{"name":"School of Science, Technology and Engineering University of the Sunshine Coast Brisbane Queensland Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kadaba S.","family":"Sriprakash","sequence":"additional","affiliation":[{"name":"School of Science &amp; Technology University of New England Armidale New South Wales Australia"},{"name":"QIMR Berghofer Medical Research Institute Brisbane Queensland Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael F.","family":"Good","sequence":"additional","affiliation":[{"name":"Institute for Biomedicine and Glycomics Griffith University Brisbane Queensland Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natkunam","family":"Ketheesan","sequence":"additional","affiliation":[{"name":"School of Science &amp; Technology University of New England Armidale New South Wales Australia"},{"name":"Institute for Biomedicine and Glycomics Griffith University Brisbane Queensland Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,7,11]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)30999-1"},{"key":"e_1_2_12_3_1","first-page":"431","volume-title":"Rheumatic Fever: How Streptococcal Throat Infection Triggers an Autoimmune Disease Infection and Autoimmunity","author":"Guilherme L.","year":"2024"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)63415-3"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2022.103209"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2020.612716"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.99.21.2784"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI7132"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2005.01.007"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.172.1.359"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.69.6.4072-4078.2001"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1080\/08916934.2016.1217999"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jix637"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1080\/08916934.2019.1605356"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/JLB.4MA0919-096RR"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2021.675339"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/ame2.12164"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/imcb.12571"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-8411(03)00026-X"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ics.2005.11.079"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.01514-08"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jim.2010.02.013"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1080\/21645515.2016.1222999"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0156639"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41541-023-00604-2"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.70.6.849"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.0818-9641.2004.01272.x"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.176.5.1483"},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.169.1.117"},{"key":"e_1_2_12_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/0090-1229(86)90096-6"},{"key":"e_1_2_12_31_1","doi-asserted-by":"publisher","DOI":"10.1080\/08916934.2017.1329831"},{"key":"e_1_2_12_32_1","doi-asserted-by":"publisher","DOI":"10.1111\/imcb.12571"},{"key":"e_1_2_12_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/ame2.12164"},{"key":"e_1_2_12_34_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.178.10.6123"},{"key":"e_1_2_12_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms11541"},{"key":"e_1_2_12_36_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1004150"},{"key":"e_1_2_12_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(05)70267-X"},{"key":"e_1_2_12_38_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.108.792135"},{"key":"e_1_2_12_39_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0173778"},{"key":"e_1_2_12_40_1","doi-asserted-by":"publisher","DOI":"10.1096\/fasebj.6.9.1612292"},{"key":"e_1_2_12_41_1","doi-asserted-by":"publisher","DOI":"10.1086\/318076"},{"key":"e_1_2_12_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1568-9972(02)00062-9"},{"key":"e_1_2_12_43_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.120.050955"},{"key":"e_1_2_12_44_1","first-page":"427","article-title":"The Effects of Pertussis Toxin on Human T Lymphocytes","volume":"64","author":"Macintyre E. A.","year":"1988","journal-title":"Immunology"},{"key":"e_1_2_12_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/0162-3109(91)90014-P"},{"key":"e_1_2_12_46_1","doi-asserted-by":"publisher","DOI":"10.2310\/JIM.0000000000000023"},{"key":"e_1_2_12_47_1","doi-asserted-by":"publisher","DOI":"10.1136\/svn-2021-000987"},{"key":"e_1_2_12_48_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.191.9.1605"},{"key":"e_1_2_12_49_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.170.4.1728"},{"key":"e_1_2_12_50_1","doi-asserted-by":"publisher","DOI":"10.1002\/1521-4141(2000)30:8<2422::AID-IMMU2422>3.0.CO;2-H"},{"key":"e_1_2_12_51_1","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/10.5.651"},{"key":"e_1_2_12_52_1","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200323675"},{"key":"e_1_2_12_53_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0007079"},{"key":"e_1_2_12_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcard.2019.04.063"},{"key":"e_1_2_12_55_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20081571"},{"key":"e_1_2_12_56_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a016295"},{"key":"e_1_2_12_57_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.00378"},{"key":"e_1_2_12_58_1","doi-asserted-by":"publisher","DOI":"10.1016\/0165-5728(93)90162-R"},{"key":"e_1_2_12_59_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.156.1.31"},{"key":"e_1_2_12_60_1","doi-asserted-by":"publisher","DOI":"10.1016\/0008-8749(82)90457-9"},{"key":"e_1_2_12_61_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.173.11.7070"},{"key":"e_1_2_12_62_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.92.3.415"},{"key":"e_1_2_12_63_1","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.69.9.5345-5351.2001"},{"key":"e_1_2_12_64_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2003.11.007"},{"key":"e_1_2_12_65_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.85851"},{"key":"e_1_2_12_66_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.carpath.2015.07.006"},{"key":"e_1_2_12_67_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2022.919700"},{"key":"e_1_2_12_68_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-50854-4"},{"key":"e_1_2_12_69_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2021.674805"}],"container-title":["Immunity, Inflammation and Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/iid3.70221","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,31]],"date-time":"2025-07-31T06:46:48Z","timestamp":1753944408000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/iid3.70221"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7]]},"references-count":68,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2025,7]]}},"alternative-id":["10.1002\/iid3.70221"],"URL":"https:\/\/doi.org\/10.1002\/iid3.70221","archive":["Portico"],"relation":{},"ISSN":["2050-4527","2050-4527"],"issn-type":[{"value":"2050-4527","type":"print"},{"value":"2050-4527","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7]]},"assertion":[{"value":"2024-11-10","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-06-19","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-07-11","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70221"}}