{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T21:14:23Z","timestamp":1790284463118,"version":"4.1.0"},"reference-count":68,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,6,24]],"date-time":"2020-06-24T00:00:00Z","timestamp":1592956800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,6,24]],"date-time":"2020-06-24T00:00:00Z","timestamp":1592956800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Post-Doctoral Training Program from Research Affairs and Graduate School, Khon Kaen University, Thailand","award":["Grant Number 59250"],"award-info":[{"award-number":["Grant Number 59250"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Patients with beta-thalassaemia increase the risk of bacterial infections, particularly <jats:italic>Burkholderia pseudomallei<\/jats:italic> (Bp), the causative agent of melioidosis in Thailand. Impaired immune cell functions may be the cause of this susceptibility, but detailed mechanisms have not been defined. In this study, we observed impaired production of IFN-gamma and IL-10 by whole blood from beta-thalassaemia patients upon stimulation with a range of bacteria-derived stimuli. In contrast, IFN-gamma response via TCR and plasma IgG specific for Bp were still intact. Importantly, mRNA expression of heme oxygenase 1 (HO-1), a potential modulator of immune function, was increased in whole blood from beta-thalassaemia patients, either with or without stimulation with Bp in vitro. Induction of HO-1 by hemin or CoPP in vitro reduced production of IFN-gamma and IL-10 from healthy human PBMCs and decreased bacterial clearance activity of whole blood from healthy controls and beta-thalassaemia, while inhibition of HO-1 by SnPP enhanced both functions in healthy controls. These results were confirmed to some extent in purified human monocytes of healthy controls. Our results suggest a mechanism that excess hemin of beta-thalassaemia patients is a significant cause of immune suppression via HO-1 induction and may underlie the susceptibility of these individuals to severe bacterial infection.<\/jats:p>","DOI":"10.1038\/s41598-020-67346-2","type":"journal-article","created":{"date-parts":[[2020,6,24]],"date-time":"2020-06-24T10:02:52Z","timestamp":1592992972000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Immune responses in beta-thalassaemia: heme oxygenase 1 reduces cytokine production and bactericidal activity of human leucocytes"],"prefix":"10.1038","volume":"10","author":[{"given":"Arnone","family":"Nithichanon","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inthira","family":"Tussakhon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Waraporn","family":"Samer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chidchamai","family":"Kewcharoenwong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manabu","family":"Ato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory J.","family":"Bancroft","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ganjana","family":"Lertmemongkolchai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,6,24]]},"reference":[{"key":"67346_CR1","doi-asserted-by":"publisher","first-page":"4331","DOI":"10.1182\/blood-2010-01-251348","volume":"115","author":"DJ Weatherall","year":"2010","unstructured":"Weatherall, D. J. The inherited diseases of hemoglobin are an emerging global health burden. Blood 115, 4331\u20134336. https:\/\/doi.org\/10.1182\/blood-2010-01-251348 (2010).","journal-title":"Blood"},{"key":"67346_CR2","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/j.ijid.2015.09.001","volume":"39","author":"N Teawtrakul","year":"2015","unstructured":"Teawtrakul, N., Jetsrisuparb, A., Sirijerachai, C., Chansung, K. & Wanitpongpun, C. Severe bacterial infections in patients with non-transfusion-dependent thalassemia: Prevalence and clinical risk factors. Int J Infect Dis 39, 53\u201356. https:\/\/doi.org\/10.1016\/j.ijid.2015.09.001 (2015).","journal-title":"Int J Infect Dis"},{"key":"67346_CR3","doi-asserted-by":"publisher","first-page":"408","DOI":"10.1086\/520223","volume":"29","author":"Y Suputtamongkol","year":"1999","unstructured":"Suputtamongkol, Y. et al. Risk factors for melioidosis and bacteremic melioidosis. Clin Infect Dis 29, 408\u2013413. https:\/\/doi.org\/10.1086\/520223 (1999).","journal-title":"Clin Infect Dis"},{"key":"67346_CR4","doi-asserted-by":"publisher","first-page":"e407","DOI":"10.1371\/journal.pntd.0000407","volume":"3","author":"P Tippayawat","year":"2009","unstructured":"Tippayawat, P. et al. Phenotypic and functional characterization of human memory T cell responses to Burkholderia pseudomallei. PLoS Negl Trop Dis 3, e407. https:\/\/doi.org\/10.1371\/journal.pntd.0000407 (2009).","journal-title":"PLoS Negl Trop Dis"},{"key":"67346_CR5","doi-asserted-by":"publisher","first-page":"198","DOI":"10.3389\/fmicb.2011.00198","volume":"2","author":"N Patel","year":"2011","unstructured":"Patel, N. et al. Development of vaccines against Burkholderia pseudomallei. Front Microbiol 2, 198. https:\/\/doi.org\/10.3389\/fmicb.2011.00198 (2011).","journal-title":"Front Microbiol"},{"key":"67346_CR6","doi-asserted-by":"publisher","first-page":"e0004152","DOI":"10.1371\/journal.pntd.0004152","volume":"9","author":"K Jenjaroen","year":"2015","unstructured":"Jenjaroen, K. et al. T-cell responses are associated with survival in acute melioidosis patients. PLoS Negl Trop Dis 9, e0004152. https:\/\/doi.org\/10.1371\/journal.pntd.0004152 (2015).","journal-title":"PLoS Negl Trop Dis"},{"key":"67346_CR7","doi-asserted-by":"publisher","first-page":"370","DOI":"10.1086\/498983","volume":"193","author":"A Haque","year":"2006","unstructured":"Haque, A. et al. Role of T cells in innate and adaptive immunity against murine Burkholderia pseudomallei infection. J Infect Dis 193, 370\u2013379. https:\/\/doi.org\/10.1086\/498983 (2006).","journal-title":"J Infect Dis"},{"key":"67346_CR8","doi-asserted-by":"publisher","first-page":"3074","DOI":"10.1128\/IAI.01733-06","volume":"75","author":"WJ Wiersinga","year":"2007","unstructured":"Wiersinga, W. J. et al. High-throughput mRNA profiling characterizes the expression of inflammatory molecules in sepsis caused by Burkholderia pseudomallei. Infect Immun 75, 3074\u20133079. https:\/\/doi.org\/10.1128\/IAI.01733-06 (2007).","journal-title":"Infect Immun"},{"key":"67346_CR9","doi-asserted-by":"publisher","first-page":"e2988","DOI":"10.1371\/journal.pntd.0002988","volume":"8","author":"M Mulye","year":"2014","unstructured":"Mulye, M. et al. Delineating the importance of serum opsonins and the bacterial capsule in affecting the uptake and killing of Burkholderia pseudomallei by murine neutrophils and macrophages. PLoS Negl Trop Dis 8, e2988. https:\/\/doi.org\/10.1371\/journal.pntd.0002988 (2014).","journal-title":"PLoS Negl Trop Dis"},{"key":"67346_CR10","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1007\/s40475-015-0042-2","volume":"2","author":"CL Hatcher","year":"2015","unstructured":"Hatcher, C. L., Muruato, L. A. & Torres, A. G. Recent advances in Burkholderia mallei and B. pseudomallei research. Curr Trop Med Rep 2, 62\u201369. https:\/\/doi.org\/10.1007\/s40475-015-0042-2 (2015).","journal-title":"Curr Trop Med Rep"},{"key":"67346_CR11","doi-asserted-by":"publisher","first-page":"3593","DOI":"10.1128\/IAI.67.7.3593-3600.1999","volume":"67","author":"P Santanirand","year":"1999","unstructured":"Santanirand, P., Harley, V. S., Dance, D. A., Drasar, B. S. & Bancroft, G. J. Obligatory role of gamma interferon for host survival in a murine model of infection with Burkholderia pseudomallei. Infect Immun 67, 3593\u20133600 (1999).","journal-title":"Infect Immun"},{"key":"67346_CR12","doi-asserted-by":"publisher","first-page":"470","DOI":"10.1128\/IAI.00930-12","volume":"81","author":"KA Hodgson","year":"2013","unstructured":"Hodgson, K. A., Govan, B. L., Walduck, A. K., Ketheesan, N. & Morris, J. L. Impaired early cytokine responses at the site of infection in a murine model of type 2 diabetes and melioidosis comorbidity. Infect Immun 81, 470\u2013477. https:\/\/doi.org\/10.1128\/IAI.00930-12 (2013).","journal-title":"Infect Immun"},{"key":"67346_CR13","first-page":"669","volume":"27","author":"H Chaudhry","year":"2013","unstructured":"Chaudhry, H. et al. Role of cytokines as a double-edged sword in sepsis. In Vivo 27, 669\u2013684 (2013).","journal-title":"In Vivo"},{"key":"67346_CR14","doi-asserted-by":"publisher","first-page":"725","DOI":"10.1189\/jlb.0509307","volume":"88","author":"CR Romero","year":"2010","unstructured":"Romero, C. R. et al. The role of interferon-gamma in the pathogenesis of acute intra-abdominal sepsis. J Leukoc Biol 88, 725\u2013735. https:\/\/doi.org\/10.1189\/jlb.0509307 (2010).","journal-title":"J Leukoc Biol"},{"key":"67346_CR15","doi-asserted-by":"publisher","first-page":"42791","DOI":"10.1038\/srep42791","volume":"7","author":"B Kessler","year":"2017","unstructured":"Kessler, B. et al. Interleukin 10 inhibits pro-inflammatory cytokine responses and killing of Burkholderia pseudomallei. Sci Rep 7, 42791. https:\/\/doi.org\/10.1038\/srep42791 (2017).","journal-title":"Sci Rep"},{"key":"67346_CR16","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmi.2019.10.032","author":"T Kaewarpai","year":"2019","unstructured":"Kaewarpai, T. et al. Longitudinal profiling of plasma cytokines in melioidosis and their association with mortality: A prospective cohort study. Clin Microbiol Infect https:\/\/doi.org\/10.1016\/j.cmi.2019.10.032 (2019).","journal-title":"Clin Microbiol Infect"},{"key":"67346_CR17","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1016\/S1473-3099(06)70437-6","volume":"6","author":"S Vento","year":"2006","unstructured":"Vento, S., Cainelli, F. & Cesario, F. Infections and thalassaemia. Lancet Infect Dis 6, 226\u2013233. https:\/\/doi.org\/10.1016\/S1473-3099(06)70437-6 (2006).","journal-title":"Lancet Infect Dis"},{"key":"67346_CR18","doi-asserted-by":"publisher","first-page":"e2009028","DOI":"10.4084\/MJHID.2009.028","volume":"1","author":"BM Ricerca","year":"2009","unstructured":"Ricerca, B. M., Di Girolamo, A. & Rund, D. Infections in thalassemia and hemoglobinopathies: Focus on therapy-related complications. Mediterr J Hematol Infect Dis 1, e2009028. https:\/\/doi.org\/10.4084\/MJHID.2009.028 (2009).","journal-title":"Mediterr J Hematol Infect Dis"},{"key":"67346_CR19","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1007\/s00277-008-0564-y","volume":"88","author":"M Gharagozloo","year":"2009","unstructured":"Gharagozloo, M., Karimi, M. & Amirghofran, Z. Double-faced cell-mediated immunity in beta-thalassemia major: Stimulated phenotype versus suppressed activity. Ann Hematol 88, 21\u201327. https:\/\/doi.org\/10.1007\/s00277-008-0564-y (2009).","journal-title":"Ann Hematol"},{"key":"67346_CR20","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1159\/000205172","volume":"83","author":"CP Speer","year":"1990","unstructured":"Speer, C. P., Gahr, M., Schuff-Werner, P. & Schroter, W. Immunologic evaluation of children with homozygous beta-thalassemia treated with desferrioxamine. Acta Haematol 83, 76\u201381 (1990).","journal-title":"Acta Haematol"},{"key":"67346_CR21","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1080\/088800102753356194","volume":"19","author":"U Ezer","year":"2002","unstructured":"Ezer, U., Gulderen, F., Culha, V. K., Akgul, N. & Gurbuz, O. Immunological status of thalassemia syndrome. Pediatr Hematol Oncol 19, 51\u201358 (2002).","journal-title":"Pediatr Hematol Oncol"},{"key":"67346_CR22","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1111\/j.1365-2141.1993.tb08659.x","volume":"85","author":"Y Matzner","year":"1993","unstructured":"Matzner, Y. et al. Impaired neutrophil chemotaxis in patients with thalassaemia major. Br J Haematol 85, 153\u2013158 (1993).","journal-title":"Br J Haematol"},{"key":"67346_CR23","first-page":"275","volume":"10","author":"MS Sternbach","year":"1987","unstructured":"Sternbach, M. S., Tsoukas, C., Paquin, M., Lajeunesse, N. & Strawczynski, H. Monocyte\u2013macrophage (M\u2013M) functions in asymptomatic hemophiliacs and supertransfused thalassemics. Clin Invest Med 10, 275\u2013281 (1987).","journal-title":"Clin Invest Med"},{"key":"67346_CR24","doi-asserted-by":"publisher","first-page":"547","DOI":"10.1111\/j.1651-2227.1981.tb05738.x","volume":"70","author":"D Sinniah","year":"1981","unstructured":"Sinniah, D. & Yadav, M. Elevated IgG and decreased complement component C3 and factor B in B-thalassaemia major. Acta Paediatr Scand 70, 547\u2013550 (1981).","journal-title":"Acta Paediatr Scand"},{"key":"67346_CR25","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1080\/1071576031000060607","volume":"37","author":"N Phumala","year":"2003","unstructured":"Phumala, N. et al. Hemin: A possible cause of oxidative stress in blood circulation of beta-thalassemia\/hemoglobin E disease. Free Radic Res 37, 129\u2013135 (2003).","journal-title":"Free Radic Res"},{"key":"67346_CR26","doi-asserted-by":"publisher","first-page":"1361","DOI":"10.1038\/ni.3590","volume":"17","author":"R Martins","year":"2016","unstructured":"Martins, R. et al. Heme drives hemolysis-induced susceptibility to infection via disruption of phagocyte functions. Nat Immunol 17, 1361\u20131372. https:\/\/doi.org\/10.1038\/ni.3590 (2016).","journal-title":"Nat Immunol"},{"key":"67346_CR27","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1111\/j.1462-5822.2008.01261.x","volume":"11","author":"SW Chung","year":"2009","unstructured":"Chung, S. W., Hall, S. R. & Perrella, M. A. Role of haem oxygenase-1 in microbial host defence. Cell Microbiol 11, 199\u2013207. https:\/\/doi.org\/10.1111\/j.1462-5822.2008.01261.x (2009).","journal-title":"Cell Microbiol"},{"key":"67346_CR28","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1146\/annurev.pharmtox.010909.105600","volume":"50","author":"R Gozzelino","year":"2010","unstructured":"Gozzelino, R., Jeney, V. & Soares, M. P. Mechanisms of cell protection by heme oxygenase-1. Annu Rev Pharmacol Toxicol 50, 323\u2013354. https:\/\/doi.org\/10.1146\/annurev.pharmtox.010909.105600 (2010).","journal-title":"Annu Rev Pharmacol Toxicol"},{"key":"67346_CR29","doi-asserted-by":"publisher","first-page":"834","DOI":"10.4049\/jimmunol.1403104","volume":"197","author":"C Stolt","year":"2016","unstructured":"Stolt, C., Schmidt, I. H., Sayfart, Y., Steinmetz, I. & Bast, A. Heme oxygenase-1 and carbon monoxide promote Burkholderia pseudomallei infection. J Immunol 197, 834\u2013846. https:\/\/doi.org\/10.4049\/jimmunol.1403104 (2016).","journal-title":"J Immunol"},{"key":"67346_CR30","doi-asserted-by":"publisher","first-page":"4641","DOI":"10.4049\/jimmunol.1500434","volume":"196","author":"CR Scharn","year":"2016","unstructured":"Scharn, C. R. et al. Heme oxygenase-1 regulates inflammation and mycobacterial survival in human macrophages during Mycobacterium tuberculosis infection. J Immunol 196, 4641\u20134649. https:\/\/doi.org\/10.4049\/jimmunol.1500434 (2016).","journal-title":"J Immunol"},{"key":"67346_CR31","doi-asserted-by":"publisher","first-page":"328","DOI":"10.1016\/j.redox.2015.01.012","volume":"4","author":"MY Abdalla","year":"2015","unstructured":"Abdalla, M. Y., Ahmad, I. M., Switzer, B. & Britigan, B. E. Induction of heme oxygenase-1 contributes to survival of Mycobacterium abscessus in human macrophages-like THP-1 cells. Redox Biol 4, 328\u2013339. https:\/\/doi.org\/10.1016\/j.redox.2015.01.012 (2015).","journal-title":"Redox Biol"},{"key":"67346_CR32","doi-asserted-by":"publisher","first-page":"2018","DOI":"10.4049\/jimmunol.166.3.2018","volume":"166","author":"E Faure","year":"2001","unstructured":"Faure, E. et al. Bacterial lipopolysaccharide and IFN-gamma induce Toll-like receptor 2 and Toll-like receptor 4 expression in human endothelial cells: role of NF-kappa B activation. J Immunol 166, 2018\u20132024 (2001).","journal-title":"J Immunol"},{"key":"67346_CR33","volume-title":"Guidelines for the Management of Transfusion Dependent Thalassaemia (TDT)","author":"MD Cappellini","year":"2014","unstructured":"Cappellini, M. D., Cohen, A., Porter, J., Taher, A. & Viprakasit, V. Guidelines for the Management of Transfusion Dependent Thalassaemia (TDT) 3rd edn. (Thalassaemia International Federation, Nicosia, 2014).","edition":"3"},{"key":"67346_CR34","doi-asserted-by":"publisher","first-page":"e0214148","DOI":"10.1371\/journal.pone.0214148","volume":"14","author":"S Chuncharunee","year":"2019","unstructured":"Chuncharunee, S., Teawtrakul, N., Siritanaratkul, N. & Chueamuangphan, N. Review of disease-related complications and management in adult patients with thalassemia: A multi-center study in Thailand. PLoS ONE 14, e0214148. https:\/\/doi.org\/10.1371\/journal.pone.0214148 (2019).","journal-title":"PLoS ONE"},{"key":"67346_CR35","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1021\/bc000055q","volume":"12","author":"T Itoh","year":"2001","unstructured":"Itoh, T. et al. Hemin (Fe(3+))- and heme (Fe(2+))-smectite conjugates as a model of hemoprotein based on spectrophotometry. Bioconjug Chem 12, 3\u20136. https:\/\/doi.org\/10.1021\/bc000055q (2001).","journal-title":"Bioconjug Chem"},{"key":"67346_CR36","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1042\/CS20180675","volume":"133","author":"PL Martin","year":"2019","unstructured":"Martin, P. L. et al. Heme oxygenase-1 induction by hemin prevents oxidative stress-induced acute cholestasis in the rat. Clin Sci (Lond) 133, 117\u2013134. https:\/\/doi.org\/10.1042\/CS20180675 (2019).","journal-title":"Clin Sci (Lond)"},{"key":"67346_CR37","doi-asserted-by":"publisher","first-page":"10287","DOI":"10.1038\/s41598-018-28488-6","volume":"8","author":"NK Campbell","year":"2018","unstructured":"Campbell, N. K. et al. Naturally derived heme-oxygenase 1 inducers attenuate inflammatory responses in human dendritic cells and T cells: Relevance for psoriasis treatment. Sci Rep 8, 10287. https:\/\/doi.org\/10.1038\/s41598-018-28488-6 (2018).","journal-title":"Sci Rep"},{"key":"67346_CR38","doi-asserted-by":"publisher","first-page":"e677","DOI":"10.1097\/PR9.0000000000000677","volume":"3","author":"K Godai","year":"2018","unstructured":"Godai, K. & Kanmura, Y. Heme oxygenase-1 inducer and carbon monoxide-releasing molecule enhance the effects of gabapentinoids by modulating glial activation during neuropathic pain in mice. Pain Rep 3, e677. https:\/\/doi.org\/10.1097\/PR9.0000000000000677 (2018).","journal-title":"Pain Rep"},{"key":"67346_CR39","doi-asserted-by":"publisher","first-page":"1573","DOI":"10.3324\/haematol.2011.055962","volume":"96","author":"F Danjou","year":"2011","unstructured":"Danjou, F., Anni, F. & Galanello, R. Beta-thalassemia: From genotype to phenotype. Haematologica 96, 1573\u20131575. https:\/\/doi.org\/10.3324\/haematol.2011.055962 (2011).","journal-title":"Haematologica"},{"key":"67346_CR40","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1016\/S0140-6736(17)31822-6","volume":"391","author":"AT Taher","year":"2018","unstructured":"Taher, A. T., Weatherall, D. J. & Cappellini, M. D. Thalassaemia . Lancet 391, 155\u2013167. https:\/\/doi.org\/10.1016\/S0140-6736(17)31822-6 (2018).","journal-title":"Lancet"},{"key":"67346_CR41","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1038\/nrendo.2009.17","volume":"5","author":"DK Singh","year":"2009","unstructured":"Singh, D. K., Winocour, P. & Farrington, K. Erythropoietic stress and anemia in diabetes mellitus. Nat Rev Endocrinol 5, 204\u2013210. https:\/\/doi.org\/10.1038\/nrendo.2009.17 (2009).","journal-title":"Nat Rev Endocrinol"},{"key":"67346_CR42","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1002\/(SICI)1097-0320(20000215)42:1<11::AID-CYTO3>3.0.CO;2-1","volume":"42","author":"K Pattanapanyasat","year":"2000","unstructured":"Pattanapanyasat, K. et al. Lymphocyte subsets and specific T-cell immune response in thalassemia. Cytometry 42, 11\u201317 (2000).","journal-title":"Cytometry"},{"key":"67346_CR43","doi-asserted-by":"publisher","first-page":"12143","DOI":"10.1038\/s41598-017-12331-5","volume":"7","author":"SJ Dunachie","year":"2017","unstructured":"Dunachie, S. J. et al. Infection with Burkholderia pseudomallei\u2014immune correlates of survival in acute melioidosis. Sci Rep 7, 12143. https:\/\/doi.org\/10.1038\/s41598-017-12331-5 (2017).","journal-title":"Sci Rep"},{"key":"67346_CR44","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1089\/107999099314243","volume":"19","author":"W Wanachiwanawin","year":"1999","unstructured":"Wanachiwanawin, W. et al. Serum levels of tumor necrosis factor-alpha, interleukin-1, and interferon-gamma in beta(o)-thalassemia\/HbE and their clinical significance. J Interferon Cytokine Res 19, 105\u2013111. https:\/\/doi.org\/10.1089\/107999099314243 (1999).","journal-title":"J Interferon Cytokine Res"},{"key":"67346_CR45","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1093\/gerona\/glu127","volume":"70","author":"E Fabbri","year":"2015","unstructured":"Fabbri, E. et al. Aging and the burden of multimorbidity: Associations with inflammatory and anabolic hormonal biomarkers. J Gerontol A Biol Sci Med Sci 70, 63\u201370. https:\/\/doi.org\/10.1093\/gerona\/glu127 (2015).","journal-title":"J Gerontol A Biol Sci Med Sci"},{"key":"67346_CR46","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1016\/j.cyto.2008.01.006","volume":"42","author":"YC Lu","year":"2008","unstructured":"Lu, Y. C., Yeh, W. C. & Ohashi, P. S. LPS\/TLR4 signal transduction pathway. Cytokine 42, 145\u2013151. https:\/\/doi.org\/10.1016\/j.cyto.2008.01.006 (2008).","journal-title":"Cytokine"},{"key":"67346_CR47","doi-asserted-by":"publisher","first-page":"17107","DOI":"10.1038\/nrdp.2017.107","volume":"4","author":"WJ Wiersinga","year":"2018","unstructured":"Wiersinga, W. J. et al. Melioidosis.  Nat Rev Dis Primers 4, 17107. https:\/\/doi.org\/10.1038\/nrdp.2017.107 (2018).","journal-title":"Nat Rev Dis Primers"},{"key":"67346_CR48","doi-asserted-by":"publisher","first-page":"4901","DOI":"10.1182\/blood-2018-99-111684","volume":"132","author":"A Tantiworawit","year":"2018","unstructured":"Tantiworawit, A. et al. The pros and cons of splenectomy in transfusion dependent thalassemia patient. Blood 132, 4901. https:\/\/doi.org\/10.1182\/blood-2018-99-111684 (2018).","journal-title":"Blood"},{"key":"67346_CR49","first-page":"192","volume":"8","author":"J Ghaffari","year":"2011","unstructured":"Ghaffari, J., Vahidshahi, K., Kosaryan, M., Soltantooyeh, Z. & Mohamadi, M. Humoral immune system state in \u03b2 thalassemia major. Med Glas (Zenica) 8, 192\u2013196 (2011).","journal-title":"Med Glas (Zenica)"},{"key":"67346_CR50","first-page":"397","volume":"62","author":"AN Akbar","year":"1985","unstructured":"Akbar, A. N., Giardina, P. J., Hilgartner, M. W. & Grady, R. W. Immunological abnormalities in thalassaemia major. I. A transfusion-related increase in circulating cytoplasmic immunoglobulin-positive cells. Clin Exp Immunol 62, 397\u2013404 (1985).","journal-title":"Clin Exp Immunol"},{"key":"67346_CR51","doi-asserted-by":"publisher","first-page":"115","DOI":"10.3389\/fphar.2014.00115","volume":"5","author":"FF Dutra","year":"2014","unstructured":"Dutra, F. F. & Bozza, M. T. Heme on innate immunity and inflammation. Front Pharmacol 5, 115. https:\/\/doi.org\/10.3389\/fphar.2014.00115 (2014).","journal-title":"Front Pharmacol"},{"key":"67346_CR52","doi-asserted-by":"publisher","first-page":"2368","DOI":"10.1182\/blood-2011-08-375303","volume":"119","author":"GB Fortes","year":"2012","unstructured":"Fortes, G. B. et al. Heme induces programmed necrosis on macrophages through autocrine TNF and ROS production. Blood 119, 2368\u20132375. https:\/\/doi.org\/10.1182\/blood-2011-08-375303 (2012).","journal-title":"Blood"},{"key":"67346_CR53","doi-asserted-by":"publisher","first-page":"18703","DOI":"10.1038\/srep18703","volume":"6","author":"C Kitatsuji","year":"2016","unstructured":"Kitatsuji, C. et al. Protein oxidation mediated by heme-induced active site conversion specific for heme-regulated transcription factor, iron response regulator. Sci Rep 6, 18703. https:\/\/doi.org\/10.1038\/srep18703 (2016).","journal-title":"Sci Rep"},{"key":"67346_CR54","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1186\/1742-2094-9-46","volume":"9","author":"S Lin","year":"2012","unstructured":"Lin, S. et al. Heme activates TLR4-mediated inflammatory injury via MyD88\/TRIF signaling pathway in intracerebral hemorrhage. J Neuroinflammation 9, 46. https:\/\/doi.org\/10.1186\/1742-2094-9-46 (2012).","journal-title":"J Neuroinflammation"},{"key":"67346_CR55","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1152\/physrev.00011.2005","volume":"86","author":"SW Ryter","year":"2006","unstructured":"Ryter, S. W., Alam, J. & Choi, A. M. Heme oxygenase-1\/carbon monoxide: From basic science to therapeutic applications. Physiol Rev 86, 583\u2013650. https:\/\/doi.org\/10.1152\/physrev.00011.2005 (2006).","journal-title":"Physiol Rev"},{"key":"67346_CR56","doi-asserted-by":"publisher","first-page":"102","DOI":"10.4049\/jimmunol.1400105","volume":"193","author":"H Zhong","year":"2014","unstructured":"Zhong, H., Bao, W., Friedman, D. & Yazdanbakhsh, K. Hemin controls T cell polarization in sickle cell alloimmunization. J Immunol 193, 102\u2013110. https:\/\/doi.org\/10.4049\/jimmunol.1400105 (2014).","journal-title":"J Immunol"},{"key":"67346_CR57","doi-asserted-by":"publisher","first-page":"4744","DOI":"10.4049\/jimmunol.172.8.4744","volume":"172","author":"HO Pae","year":"2004","unstructured":"Pae, H. O. et al. Carbon monoxide produced by heme oxygenase-1 suppresses T cell proliferation via inhibition of IL-2 production. J Immunol 172, 4744\u20134751. https:\/\/doi.org\/10.4049\/jimmunol.172.8.4744 (2004).","journal-title":"J Immunol"},{"key":"67346_CR58","doi-asserted-by":"publisher","first-page":"3449","DOI":"10.1182\/blood.V122.21.3449.3449","volume":"122","author":"DG Santos","year":"2015","unstructured":"Santos, D. G. et al. Heme oxygssenase 1 plays a role in the pathophysiology of beta-thalassemia. Blood 122, 3449 (2015).","journal-title":"Blood"},{"key":"67346_CR59","doi-asserted-by":"publisher","first-page":"1515","DOI":"10.3389\/fimmu.2018.01515","volume":"9","author":"Y Zhao","year":"2018","unstructured":"Zhao, Y. et al. Upregulation of heme oxygenase-1 endues immature dendritic cells with more potent and durable immunoregulatory properties and promotes engraftment in a stringent mouse cardiac allotransplant model. Front Immunol 9, 1515. https:\/\/doi.org\/10.3389\/fimmu.2018.01515 (2018).","journal-title":"Front Immunol"},{"key":"67346_CR60","doi-asserted-by":"publisher","first-page":"1608","DOI":"10.1093\/infdis\/jix142","volume":"215","author":"SJ Yoon","year":"2017","unstructured":"Yoon, S. J., Kim, S. J. & Lee, S. M. Overexpression of HO-1 contributes to sepsis-induced immunosuppression by modulating the Th1\/Th2 balance and regulatory t-cell function. J Infect Dis 215, 1608\u20131618. https:\/\/doi.org\/10.1093\/infdis\/jix142 (2017).","journal-title":"J Infect Dis"},{"key":"67346_CR61","doi-asserted-by":"publisher","first-page":"236","DOI":"10.1182\/blood-2017-07-798728","volume":"131","author":"D Garcia-Santos","year":"2018","unstructured":"Garcia-Santos, D. et al. Inhibition of heme oxygenase ameliorates anemia and reduces iron overload in a beta-thalassemia mouse model. Blood 131, 236\u2013246. https:\/\/doi.org\/10.1182\/blood-2017-07-798728 (2018).","journal-title":"Blood"},{"key":"67346_CR62","first-page":"1499","volume":"91","author":"K Prayongratana","year":"2008","unstructured":"Prayongratana, K., Polprasert, C., Raungrongmorakot, K., Tatone, K. & Santiwatanakul, S. Low cost combination of DCIP and MCV was better than that of DCIP and OF in the screening for hemoglobin E. J Med Assoc Thai 91, 1499\u20131504 (2008).","journal-title":"J Med Assoc Thai"},{"key":"67346_CR63","doi-asserted-by":"publisher","first-page":"1980","DOI":"10.2337\/dc11-0099","volume":"34","author":"W Aekplakorn","year":"2011","unstructured":"Aekplakorn, W. et al. Prevalence and management of diabetes and metabolic risk factors in Thai adults: the Thai National Health Examination Survey IV, 2009. Diabetes Care 34, 1980\u20131985. https:\/\/doi.org\/10.2337\/dc11-0099 (2011).","journal-title":"Diabetes Care"},{"key":"67346_CR64","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1021\/acsinfecdis.5b00118","volume":"2","author":"A Gori","year":"2016","unstructured":"Gori, A. et al. Flexible vs rigid epitope conformations for diagnostic- and vaccine-oriented applications: novel insights from the Burkholderia pseudomallei BPSL2765 Pal3 Epitope. ACS Infect Dis 2, 221\u2013230. https:\/\/doi.org\/10.1021\/acsinfecdis.5b00118 (2016).","journal-title":"ACS Infect Dis"},{"key":"67346_CR65","doi-asserted-by":"publisher","first-page":"1319","DOI":"10.1111\/febs.13223","volume":"282","author":"LJ Gourlay","year":"2015","unstructured":"Gourlay, L. J. et al. From crystal structure to in silico epitope discovery in the Burkholderia pseudomallei flagellar hook-associated protein FlgK. FEBS J 282, 1319\u20131333. https:\/\/doi.org\/10.1111\/febs.13223 (2015).","journal-title":"FEBS J"},{"key":"67346_CR66","doi-asserted-by":"publisher","first-page":"e0003917","DOI":"10.1371\/journal.pntd.0003917","volume":"9","author":"A Nithichanon","year":"2015","unstructured":"Nithichanon, A. et al. Sequence- and structure-based immunoreactive epitope discovery for Burkholderia pseudomallei flagellin. PLoS Negl Trop Dis 9, e0003917. https:\/\/doi.org\/10.1371\/journal.pntd.0003917 (2015).","journal-title":"PLoS Negl Trop Dis"},{"key":"67346_CR67","doi-asserted-by":"publisher","first-page":"3363","DOI":"10.1038\/srep03363","volume":"3","author":"C Kewcharoenwong","year":"2013","unstructured":"Kewcharoenwong, C. et al. Glibenclamide reduces pro-inflammatory cytokine production by neutrophils of diabetes patients in response to bacterial infection. Sci Rep 3, 3363. https:\/\/doi.org\/10.1038\/srep03363 (2013).","journal-title":"Sci Rep"},{"key":"67346_CR68","doi-asserted-by":"publisher","first-page":"4408","DOI":"10.4049\/jimmunol.175.7.4408","volume":"175","author":"SA Rushworth","year":"2005","unstructured":"Rushworth, S. A., Chen, X. L., Mackman, N., Ogborne, R. M. & O\u2019Connell, M. A. Lipopolysaccharide-induced heme oxygenase-1 expression in human monocytic cells is mediated via Nrf2 and protein kinase C. J Immunol 175, 4408\u20134415. https:\/\/doi.org\/10.4049\/jimmunol.175.7.4408 (2005).","journal-title":"J Immunol"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-67346-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-67346-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-67346-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,6]],"date-time":"2022-12-06T12:30:17Z","timestamp":1670329817000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-67346-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,6,24]]},"references-count":68,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["67346"],"URL":"https:\/\/doi.org\/10.1038\/s41598-020-67346-2","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,6,24]]},"assertion":[{"value":"18 December 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 June 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 June 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"10297"}}