{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T20:31:19Z","timestamp":1791923479366,"version":"4.3.4"},"reference-count":26,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,4,16]],"date-time":"2021-04-16T00:00:00Z","timestamp":1618531200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2021,4,16]],"date-time":"2021-04-16T00:00:00Z","timestamp":1618531200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["AI096925"],"award-info":[{"award-number":["AI096925"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U01AI089244"],"award-info":[{"award-number":["U01AI089244"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Med Genomics"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Cryptococcal meningitis (CM) is a major cause of death in HIV-infected patients in sub-Saharan Africa. Many CM patients experience cryptococcosis-associated immune reconstitution inflammatory syndrome (C-IRIS), which is often fatal. We sought to identify transcriptomic biomarker pathways in peripheral blood that are associated with or predict the development of death or fatal C-IRIS among patients with CM who were enrolled in the Cryptococcal Optimal ART Timing Trial.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We assessed peripheral blood gene expression using next-generation RNA sequencing in 4 groups of patients with CM: (1) no C-IRIS or Death; (2) C-IRIS survivors; (3) fatal C-IRIS; (4) Death without C-IRIS. Gene expression was assessed at the time of ART initiation, at 1, 4, and 8\u00a0weeks on ART, and at the time of C-IRIS events.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We identified 12 inflammatory and stress response pathways, including interferon type 1 signaling, that were upregulated at the time of ART initiation in patients with future fatal C-IRIS, as compared with survivors. The upregulation of transcripts involved in innate immunity (inflammasome, Toll-like receptor signaling), was observed at the time of fatal or nonfatal C-IRIS events. At the time of fatal C-IRIS events, numerous transcripts within fMLP, Rho family GTPases, HMGB1, and other acute phase response signaling pathways were upregulated, which reflects the severity of inflammation and systemic oxidative stress. Patients who died without recognized C-IRIS also had increased expression of pathways associated with oxidative stress and tissue damage.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our results showed that overactivated innate immunity, involving Toll-like receptor\/inflammasome pathways, and inflammation-induced oxidative stress, are associated with fatal outcomes. The results of this study provide insight into the molecular drivers of death and fatal C-IRIS to inform future diagnostic test development or guide targeted treatments.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12920-021-00914-1","type":"journal-article","created":{"date-parts":[[2021,4,16]],"date-time":"2021-04-16T10:34:10Z","timestamp":1618569250000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Transcriptomic biomarker pathways associated with death in HIV-infected patients with cryptococcal meningitis"],"prefix":"10.1186","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0795-4723","authenticated-orcid":false,"given":"Irina","family":"Vlasova-St Louis","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdu K.","family":"Musubire","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David B.","family":"Meya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henry W.","family":"Nabeta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hesham","family":"Mohei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David R.","family":"Boulware","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul R.","family":"Bohjanen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,4,16]]},"reference":[{"key":"914_CR1","unstructured":"Cryptococcal disease: what\u2019s new and important. WHO; 2018. https:\/\/www.who.int\/hiv\/mediacentre\/news\/cryptococcal-disease-key-messages\/en\/."},{"issue":"1","key":"914_CR2","doi-asserted-by":"publisher","first-page":"e25416","DOI":"10.1002\/jia2.25416","volume":"23","author":"MW Tenforde","year":"2020","unstructured":"Tenforde MW, Gertz AM, Lawrence DS, Wills NK, Guthrie BL, Farquhar C, Jarvis JN. Mortality from HIV-associated meningitis in sub-Saharan Africa: a systematic review and meta-analysis. J Int AIDS Soc. 2020;23(1):e25416.","journal-title":"J Int AIDS Soc"},{"issue":"11","key":"914_CR3","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1093\/ofid\/ofy267","volume":"5","author":"RKK Patel","year":"2018","unstructured":"Patel RKK, Leeme T, Azzo C, Tlhako N, Tsholo K, Tawanana EO, Molefi M, Mosepele M, Lawrence DS, Mokomane M, et al. High mortality in HIV-associated cryptococcal meningitis patients treated with amphotericin B-based therapy under routine care conditions in Africa. Open Forum Infect Dis. 2018;5(11):1\u20138.","journal-title":"Open Forum Infect Dis"},{"issue":"12","key":"914_CR4","doi-asserted-by":"publisher","first-page":"e1000384","DOI":"10.1371\/journal.pmed.1000384","volume":"7","author":"DR Boulware","year":"2010","unstructured":"Boulware DR, Meya DB, Bergemann TL, Wiesner DL, Rhein J, Musubire A, Lee SJ, Kambugu A, Janoff EN, Bohjanen PR. Clinical features and serum biomarkers in HIV immune reconstitution inflammatory syndrome after cryptococcal meningitis: a prospective cohort study. PLoS Med. 2010;7(12):e1000384.","journal-title":"PLoS Med"},{"issue":"11","key":"914_CR5","doi-asserted-by":"publisher","first-page":"791","DOI":"10.1016\/S1473-3099(10)70170-5","volume":"10","author":"LJ Haddow","year":"2010","unstructured":"Haddow LJ, Colebunders R, Meintjes G, Lawn SD, Elliott JH, Manabe YC, Bohjanen PR, Sungkanuparph S, Easterbrook PJ, French MA, et al. Cryptococcal immune reconstitution inflammatory syndrome in HIV-1-infected individuals: proposed clinical case definitions. Lancet Infect Dis. 2010;10(11):791\u2013802.","journal-title":"Lancet Infect Dis"},{"issue":"26","key":"914_CR6","doi-asserted-by":"publisher","first-page":"2487","DOI":"10.1056\/NEJMoa1312884","volume":"370","author":"DR Boulware","year":"2014","unstructured":"Boulware DR, Meya DB, Muzoora C, Rolfes MA, Huppler Hullsiek K, Musubire A, Taseera K, Nabeta HW, Schutz C, Williams DA, et al. Timing of antiretroviral therapy after diagnosis of cryptococcal meningitis. N Engl J Med. 2014;370(26):2487\u201398.","journal-title":"N Engl J Med"},{"issue":"5","key":"914_CR7","doi-asserted-by":"publisher","first-page":"769","DOI":"10.1093\/infdis\/jiv067","volume":"212","author":"JE Scriven","year":"2015","unstructured":"Scriven JE, Rhein J, Hullsiek KH, von Hohenberg M, Linder G, Rolfes MA, Williams DA, Taseera K, Meya DB, Meintjes G, et al. Early ART after cryptococcal meningitis is associated with cerebrospinal fluid pleocytosis and macrophage activation in a multisite randomized trial. J Infect Dis. 2015;212(5):769\u201378.","journal-title":"J Infect Dis"},{"issue":"4","key":"914_CR8","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1038\/nmeth.3317","volume":"12","author":"D Kim","year":"2015","unstructured":"Kim D, Langmead B, Salzberg SL. HISAT: a fast spliced aligner with low memory requirements. Nat Methods. 2015;12(4):357\u201360.","journal-title":"Nat Methods"},{"issue":"7","key":"914_CR9","doi-asserted-by":"publisher","first-page":"ofy157","DOI":"10.1093\/ofid\/ofy157","volume":"5","author":"I Vlasova-St Louis","year":"2018","unstructured":"Vlasova-St Louis I, Chang CC, Shahid S, French MA, Bohjanen PR. Transcriptomic predictors of paradoxical cryptococcosis-associated immune reconstitution inflammatory syndrome. Open Forum Infect Dis. 2018;5(7):ofy157.","journal-title":"Open Forum Infect Dis"},{"issue":"4","key":"914_CR10","doi-asserted-by":"publisher","first-page":"428","DOI":"10.1097\/QAI.0b013e3181ef4963","volume":"55","author":"DR Boulware","year":"2010","unstructured":"Boulware DR, Meya DB, Bergemann TL, Williams D, Vlasova-St Louis IA, Rhein J, Staddon J, Kambugu A, Janoff EN, Bohjanen PR. Antiretroviral therapy down-regulates innate antiviral response genes in patients with AIDS in sub-saharan Africa. J Acquir Immune Defic Syndr. 2010;55(4):428\u201338.","journal-title":"J Acquir Immune Defic Syndr"},{"issue":"3","key":"914_CR11","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1007\/s11904-017-0356-x","volume":"14","author":"CO Hileman","year":"2017","unstructured":"Hileman CO, Funderburg NT. Inflammation, immune activation, and antiretroviral therapy in HIV. Curr HIV\/AIDS Rep. 2017;14(3):93\u2013100.","journal-title":"Curr HIV\/AIDS Rep"},{"issue":"13","key":"914_CR12","doi-asserted-by":"publisher","first-page":"2089","DOI":"10.1097\/QAD.0b013e3283614a8d","volume":"27","author":"CC Chang","year":"2013","unstructured":"Chang CC, Dorasamy AA, Gosnell BI, Elliott JH, Spelman T, Omarjee S, Naranbhai V, Coovadia Y, Ndung\u2019u T, Moosa MY, et al. Clinical and mycological predictors of cryptococcosis-associated immune reconstitution inflammatory syndrome. AIDS. 2013;27(13):2089\u201399.","journal-title":"AIDS"},{"issue":"1","key":"914_CR13","first-page":"119","volume":"2","author":"H Mohei","year":"2019","unstructured":"Mohei H, Kellampalli U, Vlasova-St Louis I. Immune Reconstitution Disorders: Spotlight on Interferons. Int J Biomed Investig. 2019;2(1):119.","journal-title":"Int J Biomed Investig"},{"issue":"1","key":"914_CR14","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1186\/s12916-020-01529-6","volume":"18","author":"DM Muema","year":"2020","unstructured":"Muema DM, Akilimali NA, Ndumnego OC, Rasehlo SS, Durgiah R, Ojwach DBA, Ismail N, Dong M, Moodley A, Dong KL, et al. Association between the cytokine storm, immune cell dynamics, and viral replicative capacity in hyperacute HIV infection. BMC Med. 2020;18(1):81.","journal-title":"BMC Med"},{"issue":"1","key":"914_CR15","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/v10010001","volume":"10","author":"X Dagenais-Lussier","year":"2017","unstructured":"Dagenais-Lussier X, Loucif H, Murira A, Laulh\u00e9 X, St\u00e4ger S, Lamarre A, van Grevenynghe J. Sustained IFN-I expression during established persistent viral infection: a \u201cbad seed\u201d for protective immunity. Viruses. 2017;10(1):1\u201311.","journal-title":"Viruses"},{"issue":"9","key":"914_CR16","doi-asserted-by":"publisher","first-page":"1579","DOI":"10.1016\/j.bbadis.2014.05.031","volume":"1842","author":"I Lee","year":"2014","unstructured":"Lee I, Huttemann M. Energy crisis: the role of oxidative phosphorylation in acute inflammation and sepsis. Biochim Biophys Acta. 2014;1842(9):1579\u201386.","journal-title":"Biochim Biophys Acta"},{"key":"914_CR17","doi-asserted-by":"crossref","first-page":"1972714","DOI":"10.1155\/2018\/1972714","volume":"2018","author":"J Wang","year":"2018","unstructured":"Wang J, Song Y, Chen Z, Leng SX. Connection between systemic inflammation and neuroinflammation underlies neuroprotective mechanism of several phytochemicals in neurodegenerative diseases. Oxid Med Cell Longev. 2018;2018:1972714.","journal-title":"Oxid Med Cell Longev"},{"issue":"3","key":"914_CR18","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1093\/cvr\/cvv159","volume":"107","author":"A M\u00f3csai","year":"2015","unstructured":"M\u00f3csai A, Walzog B, Lowell CA. Intracellular signalling during neutrophil recruitment. Cardiovasc Res. 2015;107(3):373\u201385.","journal-title":"Cardiovasc Res"},{"issue":"2","key":"914_CR19","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1111\/omi.12252","volume":"34","author":"MY Zeng","year":"2019","unstructured":"Zeng MY, Miralda I, Armstrong CL, Uriarte SM, Bagaitkar J. The roles of NADPH oxidase in modulating neutrophil effector responses. Mol Oral Microbiol. 2019;34(2):27\u201338.","journal-title":"Mol Oral Microbiol"},{"key":"914_CR20","doi-asserted-by":"publisher","first-page":"725370","DOI":"10.1155\/2015\/725370","volume":"2015","author":"L Haider","year":"2015","unstructured":"Haider L. Inflammation, iron, energy failure, and oxidative stress in the pathogenesis of multiple sclerosis. Oxid Med Cell Longev. 2015;2015:725370.","journal-title":"Oxid Med Cell Longev"},{"issue":"3","key":"914_CR21","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1101\/cshperspect.a006049","volume":"4","author":"K Newton","year":"2012","unstructured":"Newton K, Dixit VM. Signaling in innate immunity and inflammation. Cold Spring Harb Perspect Biol. 2012;4(3):1\u201319.","journal-title":"Cold Spring Harb Perspect Biol"},{"key":"914_CR22","doi-asserted-by":"publisher","first-page":"3030","DOI":"10.3389\/fimmu.2019.03030","volume":"10","author":"J Westman","year":"2019","unstructured":"Westman J, Grinstein S, Marques PE. Phagocytosis of necrotic debris at sites of injury and inflammation. Front Immunol. 2019;10:3030.","journal-title":"Front Immunol"},{"key":"914_CR23","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.bbi.2015.03.010","volume":"48","author":"MG Frank","year":"2015","unstructured":"Frank MG, Weber MD, Watkins LR, Maier SF. Stress sounds the alarmin: the role of the danger-associated molecular pattern HMGB1 in stress-induced neuroinflammatory priming. Brain Behav Immun. 2015;48:1\u20137.","journal-title":"Brain Behav Immun"},{"key":"914_CR24","doi-asserted-by":"publisher","first-page":"373","DOI":"10.3389\/fcimb.2017.00373","volume":"7","author":"GT Nguyen","year":"2017","unstructured":"Nguyen GT, Green ER, Mecsas J. Neutrophils to the ROScue: mechanisms of NADPH oxidase activation and bacterial resistance. Front Cell Infect Microbiol. 2017;7:373.","journal-title":"Front Cell Infect Microbiol"},{"issue":"23","key":"914_CR25","doi-asserted-by":"publisher","first-page":"6008","DOI":"10.3390\/ijms20236008","volume":"20","author":"S Kany","year":"2019","unstructured":"Kany S, Vollrath JT, Relja B. Cytokines in inflammatory disease. Int J Mol Sci. 2019;20(23):6008.","journal-title":"Int J Mol Sci"},{"issue":"7","key":"914_CR26","doi-asserted-by":"publisher","first-page":"1126","DOI":"10.1089\/ars.2012.5149","volume":"20","author":"M Mittal","year":"2014","unstructured":"Mittal M, Siddiqui MR, Tran K, Reddy SP, Malik AB. Reactive oxygen species in inflammation and tissue injury. Antioxid Redox Signal. 2014;20(7):1126\u201367.","journal-title":"Antioxid Redox Signal"}],"container-title":["BMC Medical Genomics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12920-021-00914-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12920-021-00914-1\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12920-021-00914-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,28]],"date-time":"2024-08-28T10:47:35Z","timestamp":1724842055000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcmedgenomics.biomedcentral.com\/articles\/10.1186\/s12920-021-00914-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,16]]},"references-count":26,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["914"],"URL":"https:\/\/doi.org\/10.1186\/s12920-021-00914-1","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-50764\/v1","asserted-by":"object"}]},"ISSN":["1755-8794"],"issn-type":[{"value":"1755-8794","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,16]]},"assertion":[{"value":"31 July 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 February 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 April 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This study used deidentified pre-existing samples obtained from the COAT trial performed in Kampala, Uganda [\n                      \n                      ]. The COAT trial was approved by local Ethics Committees in Kampala, Uganda: by Uganda National Council for Science and Technology, by Mulago Hospital Research and Ethics Committee and Makerere University Infectious Diseases Institute committee (Kampala). These approvals included consents for sample collection, storage, and testing for the studies performed in this manuscript. The COAT trial was approved by the University of Minnesota IRB (# 0810M49622), by the institutional review boards at the Makerere University Infectious Diseases Institute (Uganda).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"All authors: No competed or conflicts of interest reported. All authors have read and approved the manuscript.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"108"}}