{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,8]],"date-time":"2026-02-08T04:11:36Z","timestamp":1770523896818,"version":"3.49.0"},"reference-count":39,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2023,11,22]],"date-time":"2023-11-22T00:00:00Z","timestamp":1700611200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key R&amp;D Program of China","doi-asserted-by":"publisher","award":["2021YFC230170302"],"award-info":[{"award-number":["2021YFC230170302"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>While purified protein derivative (PPD) is commonly used as skin diagnostic reagent for tuberculosis (TB) infection, it cannot distinguish effectively Bacillus Calmette\u2013Gu\u00e9rin (BCG) vaccination from Mycobacterium tuberculosis (MTB) complex and nontuberculous mycobacteria infection. The new skin reagent ESAT6-CFP10 (EC) has favorable sensitivity and specificity, which can overcome limitations associated with PPD. At present, EC skin test reactions are mainly characterized by erythema, while PPD mainly causes induration. We conducted a comparative study on the potential differences between EC-induced erythema and PPD-induced induration using a guinea pig model. The size of EC-dependent erythema was similar to that of PPD-induced induration, and an inflammatory response characterized by the infiltration of monocytes, macrophages and lymphocytes, as well as tissue damage, appeared at the injection site. The lymphocytes included CD4+ T and CD8+ T cells, which released IFN-\u03b3 as the main cytokine. Both EC erythema and PPD induration could lead to increased levels of acute-phase proteins, and the differential pathways were similar, thus indicating that the main induced immune pathways were similar. The above results indicated that erythema produced by EC could generate the main delayed-type hypersensitivity (DTH) response characteristic of PPD induration, thereby suggesting that erythema might also have a certain diagnostic significance and provide a possible theoretical basis for its use as a diagnostic indicator for detecting MTB infection.<\/jats:p>","DOI":"10.3390\/ijms242316612","type":"journal-article","created":{"date-parts":[[2023,11,22]],"date-time":"2023-11-22T08:47:43Z","timestamp":1700642863000},"page":"16612","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["A Comparative Study on the Mechanism of Delayed-Type Hypersensitivity Mediated by the Recombinant Mycobacterium tuberculosis Fusion Protein ESAT6-CFP10 and Purified Protein Derivative"],"prefix":"10.3390","volume":"24","author":[{"given":"Xiaonan","family":"Guo","sequence":"first","affiliation":[{"name":"National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun 130012, China"},{"name":"Division of Tuberculosis Vaccine and Allergen Products, Institute of Biological Product Control, National Institutes for Food and Drug Control, Beijing 102629, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weixin","family":"Du","sequence":"additional","affiliation":[{"name":"Division of Tuberculosis Vaccine and Allergen Products, Institute of Biological Product Control, National Institutes for Food and Drug Control, Beijing 102629, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5542-3375","authenticated-orcid":false,"given":"Junli","family":"Li","sequence":"additional","affiliation":[{"name":"Division of Tuberculosis Vaccine and Allergen Products, Institute of Biological Product Control, National Institutes for Food and Drug Control, Beijing 102629, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiaxin","family":"Dong","sequence":"additional","affiliation":[{"name":"Division of Tuberculosis Vaccine and Allergen Products, Institute of Biological Product Control, National Institutes for Food and Drug Control, Beijing 102629, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaobing","family":"Shen","sequence":"additional","affiliation":[{"name":"Division of Tuberculosis Vaccine and Allergen Products, Institute of Biological Product Control, National Institutes for Food and Drug Control, Beijing 102629, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cheng","family":"Su","sequence":"additional","affiliation":[{"name":"Division of Tuberculosis Vaccine and Allergen Products, Institute of Biological Product Control, National Institutes for Food and Drug Control, Beijing 102629, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aihua","family":"Zhao","sequence":"additional","affiliation":[{"name":"Division of Tuberculosis Vaccine and Allergen Products, Institute of Biological Product Control, National Institutes for Food and Drug Control, Beijing 102629, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yongge","family":"Wu","sequence":"additional","affiliation":[{"name":"National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun 130012, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miao","family":"Xu","sequence":"additional","affiliation":[{"name":"Division of Tuberculosis Vaccine and Allergen Products, Institute of Biological Product Control, National Institutes for Food and Drug Control, Beijing 102629, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/j.ijtb.2020.02.005","article-title":"A systemic review on tuberculosis","volume":"67","author":"Natarajan","year":"2020","journal-title":"Indian J. Tuberc."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1204","DOI":"10.1016\/S0140-6736(20)30925-9","article-title":"Global burden of 369 diseases and injuries in 204 countries and territories, 1990\u20132019: A systematic analysis for the Global Burden of Disease Study 2019","volume":"396","author":"Diseases","year":"2020","journal-title":"Lancet"},{"key":"ref_3","unstructured":"(2022, October 27). Available online: https:\/\/www.who.int\/publications\/i\/item\/9789240061729."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1900655","DOI":"10.1183\/13993003.00655-2019","article-title":"The global prevalence of latent tuberculosis: A systematic review and me-ta-analysis","volume":"54","author":"Cohen","year":"2019","journal-title":"Eur. Respir. J."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Houben, R.M.G.J., and Dodd, P.J. (2016). The Global Burden of Latent Tuberculosis Infection: A Re-estimation Using Mathematical Modelling. PLoS Med., 13.","DOI":"10.1371\/journal.pmed.1002152"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1016\/S1473-3099(17)30402-4","article-title":"Incidence of active tuberculosis in individuals with latent tuberculosis infection in rural China: Follow-up results of a population-based, multicentre, prospective cohort study","volume":"17","author":"Gao","year":"2017","journal-title":"Lancet Infect. Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"S37","DOI":"10.1016\/j.ijid.2020.02.034","article-title":"Management of latent tuberculosis infection in China: Exploring solutions suitable for high-burden countries","volume":"92S","author":"Cui","year":"2020","journal-title":"Int. J. Infect. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1799","DOI":"10.1016\/S0140-6736(15)60570-0","article-title":"WHO\u2019s new end TB strategy","volume":"385","author":"Uplekar","year":"2015","journal-title":"Lancet"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1093\/clinids\/17.6.968","article-title":"The tuberculin skin test","volume":"17","author":"Huebner","year":"1993","journal-title":"Clin. Infect. Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1111\/j.1574-695X.2012.01002.x","article-title":"Purified protein derivatives of tuberculin--past, present, and future","volume":"66","author":"Yang","year":"2012","journal-title":"FEMS Immunol. Med. Microbiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1128\/CMR.00034-13","article-title":"Gamma interferon release assays for detection of Mycobacterium tuberculosis infec-tion","volume":"27","author":"Pai","year":"2014","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/j.jegh.2013.06.003","article-title":"Providing detailed information about latent tuberculosis and compliance with the PPD test among healthcare workers in Israel: A randomized controlled study","volume":"3","author":"Taubman","year":"2013","journal-title":"J. Epidemiol. Glob. Health"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/S2213-2600(16)30436-2","article-title":"Safety and efficacy of the C-Tb skin test to diagnose Mycobacterium tu-berculosis infection, compared with an interferon gamma release assay and the tuberculin skin test: A phase 3, double-blind, randomised, controlled trial","volume":"5","author":"Ruhwald","year":"2017","journal-title":"Lancet Respir. Med."},{"key":"ref_14","unstructured":"(2022). WHO Operational Handbook on Tuberculosis: Module 3: Diagnosis: Tests for Tuberculosis Infection."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"889.e9","DOI":"10.1016\/j.cmi.2016.07.015","article-title":"Recombinant fusion ESAT6-CFP10 immunogen as a skin test reagent for tuberculosis diagnosis: An open-label, randomized, two-centre phase 2a clinical trial","volume":"22","author":"Li","year":"2016","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1046\/j.1365-2958.2003.03844.x","article-title":"Individual RD1-region genes are required for export of ESAT-6\/CFP-10 and for virulence of Mycobacterium tuberculosis","volume":"51","author":"Guinn","year":"2004","journal-title":"Mol. Microbiol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Slogotskaya, L., Bogorodskaya, E., Ivanova, D., and Sevostyanova, T. (2018). Comparative sensitivity of the test with tuberculosis recombinant aller-gen, containing ESAT6-CFP10 protein, and Mantoux test with 2 TU PPD-L in newly diagnosed tuberculosis children and ad-olescents in Moscow. PLoS ONE, 13.","DOI":"10.1101\/343665"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1803","DOI":"10.3389\/fimmu.2017.01803","article-title":"MTBVAC: Attenuating the Human Pathogen of Tuberculosis (TB) toward a Promising Vaccine against the TB Epidemic","volume":"8","author":"Marinova","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1128\/CVI.00154-16","article-title":"Safety of Recombinant Fusion Protein ESAT6-CFP10 as a Skin Test Reagent for Tuberculosis Diagnosis: An Open-Label, Randomized, Single-Center Phase I Clinical Trial","volume":"23","author":"Li","year":"2016","journal-title":"Clin. Vaccine Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"ofad228","DOI":"10.1093\/ofid\/ofad228","article-title":"A Systematic Review on the Safety of Mycobacterium tuberculosis\u2013Specific Antigen\u2013Based Skin Tests for Tuberculosis Infection Compared With Tuberculin Skin Tests","volume":"10","author":"Hamada","year":"2023","journal-title":"Open Forum Infect. Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1093\/cid\/ciab472","article-title":"Sensitivity, Specificity, and Safety of a Novel ESAT6-CFP10 Skin Test for Tuberculosis Infection in China: 2 Randomized, Self-Controlled, Parallel-Group Phase 2b Trials","volume":"74","author":"Xu","year":"2022","journal-title":"Clin. Infect. Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.ijid.2022.11.014","article-title":"High accuracy of recombinant fusion protein early secretory antigenic target protein 6-culture filtrate protein 10 skin test for the detection of tuberculosis infection: A phase III, multi-centered, double-blind, hospital-based, randomized controlled trial","volume":"126","author":"Xia","year":"2023","journal-title":"Int. J. Infect. Dis."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4326","DOI":"10.1128\/JCM.01184-06","article-title":"Optimizing antigen cocktails for detection of Mycobacterium bovis in herds with different prevalences of bovine tuberculosis: ESAT6-CFP10 mixture shows optimal sensitivity and specificity","volume":"44","author":"Aagaard","year":"2006","journal-title":"J. Clin. Microbiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1161526","DOI":"10.3389\/fphar.2023.1161526","article-title":"Long-term economic evaluation of the recombinant Mycobacterium tuberculosis fusion protein (EC) test for the diagnosis of Mycobacterium tuberculosis infection","volume":"14","author":"Diao","year":"2023","journal-title":"Front. Pharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Zhang, H., Wang, L., Li, F., Lu, S., and Xia, J. (2020). Induration or erythema diameter not less than 5 mm as results of recombinant fusion protein ESAT6-CFP10 skin test for detecting M. tuberculosis infection. BMC Infect. Dis., 20.","DOI":"10.1186\/s12879-020-05413-9"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1016\/S2213-2600(17)30012-7","article-title":"C-Tb: A latent tuberculosis skin test for the 21st century?","volume":"5","author":"Abubakar","year":"2017","journal-title":"Lancet Respir. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"872676","DOI":"10.3389\/fimmu.2022.872676","article-title":"In Vitro and In Vivo Antigen Presentation and Diagnosis Development of Recombinant Overlapping Peptides Corresponding to Mtb ESAT-6\/CFP-10","volume":"13","author":"Zhang","year":"2022","journal-title":"Front. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Druszczynska, M., Wlodarczyk, M., Kielnierowski, G., Seweryn, M., Wawrocki, S., and Rudnicka, W. (2017). CD14-159C\/T polymorphism in the development of delayed skin hypersensitivity to tuberculin. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0190106"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"7","DOI":"10.5070\/D32FW0G1XX","article-title":"Delayed type hypersensitivity: Current theories with an historic perspective","volume":"5","author":"Black","year":"1999","journal-title":"Dermatol. Online J."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1128\/IAI.00486-10","article-title":"Three protein cocktails mediate delayed-type hypersensitivity responses indistinguishable from that elicited by purified protein derivative in the guinea pig model of Mycobacterium tuberculosis infection","volume":"79","author":"Yang","year":"2011","journal-title":"Infect. Immun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1016\/S0091-6749(99)70489-6","article-title":"Molecular mechanisms of CD8+ T cell-mediated delayed hypersensitivity: Implications for allergies, asthma, and autoimmunity","volume":"103","author":"Kalish","year":"1999","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1302","DOI":"10.1172\/JCI109425","article-title":"Delayed-type hypersensitivity skin reactions in congenital afibrinogenemia lack fibrin deposition and induration","volume":"63","author":"Colvin","year":"1979","journal-title":"J. Clin. Investig."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1111\/exd.12111","article-title":"E-FABP induces differentiation in normal human keratinocytes and modulates the differentiation process in psoriatic keratinocytes in vitro","volume":"22","author":"Dallaglio","year":"2013","journal-title":"Exp. Dermatol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Hardy, L.M., Frisdal, E., and Le Goff, W. (2017). Critical Role of the Human ATP-Binding Cassette G1 Transporter in Cardiometabolic Diseases. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18091892"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"S26","DOI":"10.1097\/CCM.0b013e3181c98d21","article-title":"Inflammation and coagulation","volume":"38","author":"Levi","year":"2010","journal-title":"Crit. Care Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/0003-2697(76)90527-3","article-title":"A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding","volume":"72","author":"Bradford","year":"1976","journal-title":"Anal. Biochem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/75556","article-title":"Gene ontology: Tool for the unification of biology","volume":"25","author":"Ashburner","year":"2000","journal-title":"Nat. Genet."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"D277","DOI":"10.1093\/nar\/gkh063","article-title":"The KEGG resource for deciphering the genome","volume":"32","author":"Kanehisa","year":"2004","journal-title":"Nucleic Acids Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/23\/16612\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:27:10Z","timestamp":1760131630000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/23\/16612"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,22]]},"references-count":39,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["ijms242316612"],"URL":"https:\/\/doi.org\/10.3390\/ijms242316612","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,22]]}}}