{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T13:08:27Z","timestamp":1791637707432,"version":"4.3.4"},"reference-count":51,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2025,9,8]],"date-time":"2025-09-08T00:00:00Z","timestamp":1757289600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100019637","name":"Horizon Therapeutics","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100019637","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Stacy True Memorial Trust Fund"},{"name":"Marranzino and Morgan families"},{"name":"NIH\/NCATS","award":["UL1 TR002535"],"award-info":[{"award-number":["UL1 TR002535"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>Interferon-gamma (IFN-\u03b3) decreases infections in chronic granulomatous disease (CGD) with variably incomplete restoration of the fundamental CGD defect, converting oxygen to microbicidal oxidants during phagocytosis. We sought to understand other IFN-\u03b3 effects that could contribute to protection of CGD patients. We measured neutrophil function, gene expression, and biochemical parameters in nine CGD patients off IFN-\u03b3 and 10\u201312 hours after the first (1st) and fourth (4th) IFN-\u03b3 injection. Non-directed motility and bactericidal activity increased after IFN-\u03b3 administration; ingestion remained unchanged. Stimulated release of superoxide anion (O<jats:sub>2<\/jats:sub><jats:sup>-<\/jats:sup>) was minimally changed. Treatment decreased expression of 483 genes and increased 386. Expression of eleven genes associated with neutrophil activity was upregulated. Genes not routinely associated with neutrophil function also demonstrated increased expression, including MHCI &amp; II proteins, guanylate-binding proteins, and an enzyme synthesizing a nitric-oxide (NO) synthetase cofactor. CD11b expression, F-actin assembly, and CD 274 antigen were increased after treatment as was NO in neutrophil lysates. Formation of neutrophil extracellular traps after ingestion of staphylococci was increased off IFN-\u03b3 compared with controls but moved toward normal after IFN-\u03b3 administration. IFN-\u03b3 protects against infection in CGD by several mechanisms that could potentially support others with compromised host defense.<\/jats:p>\n<jats:sec id=\"sec001\">\n<jats:title>Trial registration<\/jats:title>\n<jats:p>ClinicalTrials.gov NCT03548818<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0331657","type":"journal-article","created":{"date-parts":[[2025,9,8]],"date-time":"2025-09-08T17:43:22Z","timestamp":1757353402000},"page":"e0331657","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["Interferon-gamma 1b-induced gene expression alters neutrophil function in patients with chronic granulomatous disease"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7049-354X","authenticated-orcid":true,"given":"Daniel R.","family":"Ambruso","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie J.","family":"Briones","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander D.","family":"Tran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2173-0198","authenticated-orcid":true,"given":"Bridget","family":"Sanford","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Childs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0149-2388","authenticated-orcid":true,"given":"Ben Z.","family":"Katz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Ellison","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard B.","family":"Johnston","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth L.","family":"Jones","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,9,8]]},"reference":[{"issue":"87","key":"pone.0331657.ref001","first-page":"123","article-title":"Interferon-\u03b3 and systemic autoimmunity","volume":"16","author":"KM Pollard","year":"2013","journal-title":"Discov Med"},{"key":"pone.0331657.ref002","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/S0065-2776(07)96002-2","article-title":"Regulation of interferon-gamma during innate and adaptive immune responses","volume":"96","author":"JR Schoenborn","year":"2007","journal-title":"Adv Immunol"},{"issue":"34","key":"pone.0331657.ref003","doi-asserted-by":"crossref","first-page":"13925","DOI":"10.1074\/jbc.R116.774745","article-title":"Current prospects of type II interferon \u03b3 signaling and autoimmunity","volume":"292","author":"DS Green","year":"2017","journal-title":"J Biol Chem"},{"issue":"6552","key":"pone.0331657.ref004","doi-asserted-by":"crossref","DOI":"10.1126\/science.abf8113","article-title":"A human apolipoprotein L with detergent-like activity kills intracellular pathogens","volume":"373","author":"RG Gaudet","year":"2021","journal-title":"Science"},{"issue":"2","key":"pone.0331657.ref005","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0263370","article-title":"In vivo interferon-gamma induced changes in gene expression dramatically alter neutrophil phenotype","volume":"17","author":"DR Ambruso","year":"2022","journal-title":"PLoS One"},{"issue":"1","key":"pone.0331657.ref006","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1111\/j.1365-2567.2004.01849.x","article-title":"Interferon-gamma activation of polymorphonuclear neutrophil function","volume":"112","author":"TN Ellis","year":"2004","journal-title":"Immunology"},{"issue":"8","key":"pone.0331657.ref007","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0136766","article-title":"INF-\u03b3 Enhances Nox2 Activity by Upregulating phox Proteins When Applied to Differentiating PLB-985 Cells but Does Not Induce Nox2 Activity by Itself","volume":"10","author":"MA Ellison","year":"2015","journal-title":"PLoS One"},{"issue":"10","key":"pone.0331657.ref008","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0185956","article-title":"IFN-\u03b3 alters the expression of diverse immunity related genes in a cell culture model designed to represent maturing neutrophils","volume":"12","author":"MA Ellison","year":"2017","journal-title":"PLoS One"},{"issue":"4","key":"pone.0331657.ref009","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1172\/JCI113153","article-title":"Recombinant interferon gamma augments phagocyte superoxide production and X-chronic granulomatous disease gene expression in X-linked variant chronic granulomatous disease","volume":"80","author":"RA Ezekowitz","year":"1987","journal-title":"J Clin Invest"},{"issue":"3","key":"pone.0331657.ref010","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1056\/NEJM198807213190305","article-title":"Partial correction of the phagocyte defect in patients with X-linked chronic granulomatous disease by subcutaneous interferon gamma","volume":"319","author":"RA Ezekowitz","year":"1988","journal-title":"N Engl J Med"},{"issue":"13","key":"pone.0331657.ref011","doi-asserted-by":"crossref","first-page":"4874","DOI":"10.1073\/pnas.85.13.4874","article-title":"Recombinant human interferon-gamma reconstitutes defective phagocyte function in patients with chronic granulomatous disease of childhood","volume":"85","author":"JM Sechler","year":"1988","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"27","key":"pone.0331657.ref012","doi-asserted-by":"crossref","first-page":"2600","DOI":"10.1056\/NEJMoa1007097","article-title":"Residual NADPH oxidase and survival in chronic granulomatous disease","volume":"363","author":"DB Kuhns","year":"2010","journal-title":"N Engl J Med"},{"key":"pone.0331657.ref013","volume-title":"The neutrophil: function and clinical disorders","author":"SJ Klebanoff","year":"1978"},{"key":"pone.0331657.ref014","first-page":"769","article-title":"The respiratory burst oxidase.","volume-title":"Inflammation: Basic Principles and Clinical Correlates","author":"TL. Leto","year":"1999"},{"key":"pone.0331657.ref015","doi-asserted-by":"crossref","unstructured":"Ambruso DR, Hauk PJ. Primary Immunodeficiency and Other Diseases With Immune Dysregulation. Kendig\u2019s Disorders of the Respiratory Tract in Children. 2019. p. 909\u201322.e5.","DOI":"10.1016\/B978-0-323-44887-1.00063-8"},{"issue":"7","key":"pone.0331657.ref016","doi-asserted-by":"crossref","first-page":"4030","DOI":"10.4049\/jimmunol.1001778","article-title":"Impaired phagocytosis of apoptotic cells by macrophages in chronic granulomatous disease is reversed by IFN-gamma in a nitric oxide-dependent manner","volume":"185","author":"R Fernandez-Boyanapalli","year":"2010","journal-title":"J Immunol"},{"issue":"8","key":"pone.0331657.ref017","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1056\/NEJM199102213240801","article-title":"A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease","volume":"324","author":"Group International Chronic Granulomatous Disease Cooperative Study","year":"1991","journal-title":"N Engl J Med"},{"issue":"5","key":"pone.0331657.ref018","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1086\/422993","article-title":"Long-term interferon-gamma therapy for patients with chronic granulomatous disease","volume":"39","author":"BE Marciano","year":"2004","journal-title":"Clin Infect Dis"},{"issue":"3","key":"pone.0331657.ref019","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1093\/infdis\/162.3.723","article-title":"Trimethoprim-sulfamethoxazole prophylaxis in the management of chronic granulomatous disease","volume":"162","author":"DM Margolis","year":"1990","journal-title":"J Infect Dis"},{"issue":"24","key":"pone.0331657.ref020","doi-asserted-by":"crossref","first-page":"2416","DOI":"10.1056\/NEJMoa021931","article-title":"Itraconazole to prevent fungal infections in chronic granulomatous disease","volume":"348","author":"JI Gallin","year":"2003","journal-title":"N Engl J Med"},{"issue":"7","key":"pone.0331657.ref021","doi-asserted-by":"crossref","first-page":"1411","DOI":"10.1007\/s10875-022-01294-6","article-title":"Chronic Granulomatous Disease: an Updated Experience, with Emphasis on Newly Recognized Features","volume":"42","author":"Z Oikonomopoulou","year":"2022","journal-title":"J Clin Immunol"},{"issue":"11","key":"pone.0331657.ref022","doi-asserted-by":"crossref","first-page":"4366","DOI":"10.1182\/blood.V92.11.4366","article-title":"In vivo treatment with granulocyte colony-stimulating factor results in divergent effects on neutrophil functions measured in vitro","volume":"92","author":"PJ Leavey","year":"1998","journal-title":"Blood"},{"issue":"9","key":"pone.0331657.ref023","doi-asserted-by":"crossref","first-page":"4654","DOI":"10.1073\/pnas.080074897","article-title":"Human neutrophil immunodeficiency syndrome is associated with an inhibitory Rac2 mutation","volume":"97","author":"DR Ambruso","year":"2000","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"23","key":"pone.0331657.ref024","doi-asserted-by":"crossref","first-page":"5888","DOI":"10.1182\/bloodadvances.2020002225","article-title":"Metabolic abnormalities in G6PC3-deficient human neutrophils result in severe functional defects","volume":"4","author":"C McKinney","year":"2020","journal-title":"Blood Adv"},{"issue":"2","key":"pone.0331657.ref025","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/0022-1759(89)90209-3","article-title":"Flow cytometric assay for the measurement of serum opsonins to Neisseria meningitidis serogroup B, serotype 15","volume":"116","author":"H Sjursen","year":"1989","journal-title":"J Immunol Methods"},{"key":"pone.0331657.ref026","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/0022-1759(83)90340-X","article-title":"Differentiation between attached and ingested immune complexes by a fluorescence quenching cytofluorometric assay","volume":"60","author":"S Sahlin","year":"1983","journal-title":"J Immunol Methods"},{"issue":"8","key":"pone.0331657.ref027","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1002\/cyto.a.23169","article-title":"Measurement of NET formation in vitro and in vivo by flow cytometry","volume":"91","author":"S Masuda","year":"2017","journal-title":"Cytometry A"},{"issue":"12","key":"pone.0331657.ref028","doi-asserted-by":"crossref","first-page":"7413","DOI":"10.4049\/jimmunol.1000675","article-title":"A novel mechanism of rapid nuclear neutrophil extracellular trap formation in response to Staphylococcus aureus","volume":"185","author":"FH Pilsczek","year":"2010","journal-title":"J Immunol"},{"issue":"6","key":"pone.0331657.ref029","doi-asserted-by":"crossref","first-page":"1609","DOI":"10.1002\/eji.201142157","article-title":"Phox activity of differentiated PLB-985 cells is enhanced, in an agonist specific manner, by the PLA2 activity of Prdx6-PLA2","volume":"42","author":"MA Ellison","year":"2012","journal-title":"Eur J Immunol"},{"issue":"2","key":"pone.0331657.ref030","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1016\/j.bbamcr.2011.11.014","article-title":"Peroxiredoxin 6 translocates to the plasma membrane during neutrophil activation and is required for optimal NADPH oxidase activity","volume":"1823","author":"DR Ambruso","year":"2012","journal-title":"Biochim Biophys Acta"},{"issue":"10","key":"pone.0331657.ref031","doi-asserted-by":"crossref","first-page":"5877","DOI":"10.1128\/JVI.00476-14","article-title":"Comparison of varicella-zoster virus RNA sequences in human neurons and fibroblasts","volume":"88","author":"NL Baird","year":"2014","journal-title":"J Virol"},{"issue":"7","key":"pone.0331657.ref032","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1093\/bioinformatics\/btq057","article-title":"Fast and SNP-tolerant detection of complex variants and splicing in short reads","volume":"26","author":"TD Wu","year":"2010","journal-title":"Bioinformatics"},{"issue":"5","key":"pone.0331657.ref033","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1038\/nbt.1621","article-title":"Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation","volume":"28","author":"C Trapnell","year":"2010","journal-title":"Nat Biotechnol"},{"issue":"2","key":"pone.0331657.ref034","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1007\/BF00916022","article-title":"Studies of phagocytosis in chronic granulomatous disease","volume":"11","author":"TA Gaither","year":"1987","journal-title":"Inflammation"},{"issue":"4","key":"pone.0331657.ref035","first-page":"291","article-title":"Increased phagocytic activity of polymorphonuclear leukocytes of chronic granulomatous disease as determined with flow cytometric assay","volume":"117","author":"M Hasui","year":"1991","journal-title":"J Lab Clin Med"},{"issue":"9","key":"pone.0331657.ref036","doi-asserted-by":"crossref","first-page":"2817","DOI":"10.1073\/pnas.1414055112","article-title":"SK3 channel and mitochondrial ROS mediate NADPH oxidase-independent NETosis induced by calcium influx","volume":"112","author":"DN Douda","year":"2015","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"5","key":"pone.0331657.ref037","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1083\/jcb.201203170","article-title":"Neutrophil extracellular traps: is immunity the second function of chromatin?","volume":"198","author":"V Brinkmann","year":"2012","journal-title":"J Cell Biol"},{"issue":"4","key":"pone.0331657.ref038","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1046\/j.1365-2567.2000.00140.x","article-title":"Polymorphonuclear neutrophils as accessory cells for T-cell activation: major histocompatibility complex class II restricted antigen-dependent induction of T-cell proliferation","volume":"101","author":"M Radsak","year":"2000","journal-title":"Immunology"},{"issue":"11","key":"pone.0331657.ref039","doi-asserted-by":"crossref","first-page":"4128","DOI":"10.1182\/blood.V89.11.4128","article-title":"Activation of human T cells by major histocompatability complex class II expressing neutrophils: proliferation in the presence of superantigen, but not tetanus toxoid","volume":"89","author":"NA Fanger","year":"1997","journal-title":"Blood"},{"issue":"3","key":"pone.0331657.ref040","doi-asserted-by":"crossref","first-page":"1482","DOI":"10.4049\/jimmunol.151.3.1482","article-title":"Induction of MHC class II on human polymorphonuclear neutrophils by granulocyte\/macrophage colony-stimulating factor, IFN-gamma, and IL-3","volume":"151","author":"EJ Gosselin","year":"1993","journal-title":"J Immunol"},{"issue":"4","key":"pone.0331657.ref041","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1189\/jlb.1MR1014-502R","article-title":"Neutrophil plasticity: acquisition of phenotype and functionality of antigen-presenting cell","volume":"98","author":"A Takashima","year":"2015","journal-title":"J Leukoc Biol"},{"issue":"5","key":"pone.0331657.ref042","doi-asserted-by":"crossref","first-page":"2538","DOI":"10.4049\/jimmunol.167.5.2538","article-title":"Neutrophils process exogenous bacteria via an alternate class I MHC processing pathway for presentation of peptides to T lymphocytes","volume":"167","author":"NS Potter","year":"2001","journal-title":"J Immunol"},{"issue":"2","key":"pone.0331657.ref043","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1002\/jlb.60.2.207","article-title":"Polymorphonuclear neutrophils pulsed with synthetic peptides efficiently activate memory cytotoxic T lymphocytes","volume":"60","author":"E Reali","year":"1996","journal-title":"J Leukoc Biol"},{"issue":"12","key":"pone.0331657.ref044","doi-asserted-by":"crossref","first-page":"4286","DOI":"10.4049\/jimmunol.140.12.4286","article-title":"Selective synthesis of mRNA and proteins by human peripheral blood neutrophils","volume":"140","author":"RM Jack","year":"1988","journal-title":"J Immunol"},{"issue":"11","key":"pone.0331657.ref045","doi-asserted-by":"crossref","first-page":"3520","DOI":"10.4049\/jimmunol.148.11.3520","article-title":"Regulation of MHC class I synthesis and expression by human neutrophils","volume":"148","author":"E Neuman","year":"1992","journal-title":"J Immunol"},{"issue":"5","key":"pone.0331657.ref046","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/0167-5699(92)90121-M","article-title":"Poly\u2019s lament: the neglected role of the polymorphonuclear neutrophil in the afferent limb of the immune response","volume":"13","author":"AR Lloyd","year":"1992","journal-title":"Immunol Today"},{"issue":"8","key":"pone.0331657.ref047","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0006499","article-title":"Human guanylate binding proteins potentiate the anti-chlamydia effects of interferon-gamma","volume":"4","author":"I Tietzel","year":"2009","journal-title":"PLoS One"},{"issue":"6030","key":"pone.0331657.ref048","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1126\/science.1201711","article-title":"A family of IFN-\u03b3-inducible 65-kD GTPases protects against bacterial infection","volume":"332","author":"B-H Kim","year":"2011","journal-title":"Science"},{"issue":"3","key":"pone.0331657.ref049","doi-asserted-by":"crossref","first-page":"271","DOI":"10.4161\/viru.20328","article-title":"The potential of nitric oxide releasing therapies as antimicrobial agents","volume":"3","author":"DO Schairer","year":"2012","journal-title":"Virulence"},{"issue":"2","key":"pone.0331657.ref050","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1172\/JCI115903","article-title":"Evidence for reactive nitrogen intermediates in killing of staphylococci by human neutrophil cytoplasts. A new microbicidal pathway for polymorphonuclear leukocytes","volume":"90","author":"SE Malawista","year":"1992","journal-title":"J Clin Invest"},{"issue":"2","key":"pone.0331657.ref051","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1189\/jlb.5BT0615-234R","article-title":"At the Bedside: Neutrophil extracellular traps (NETs) as targets for biomarkers and therapies in autoimmune diseases","volume":"99","author":"A Barnado","year":"2016","journal-title":"J Leukoc Biol"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0331657","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,8]],"date-time":"2025-09-08T17:43:52Z","timestamp":1757353432000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0331657"}},"subtitle":[],"editor":[{"given":"Partha","family":"Mukhopadhyay","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2025,9,8]]},"references-count":51,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,9,8]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0331657","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,8]]}}}