{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T02:42:37Z","timestamp":1760150557578,"version":"build-2065373602"},"reference-count":46,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2023,12,7]],"date-time":"2023-12-07T00:00:00Z","timestamp":1701907200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Consejo Nacional de Ciencia y Tecnolog\u00eda (CONACyT)","award":["385001","Fon Inst.\/58\/2016"],"award-info":[{"award-number":["385001","Fon Inst.\/58\/2016"]}]},{"name":"CONACyT project","award":["385001","Fon Inst.\/58\/2016"],"award-info":[{"award-number":["385001","Fon Inst.\/58\/2016"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Microorganisms"],"abstract":"<jats:p>Mycobacterium tuberculosis is the main causal agent of pulmonary tuberculosis (TB); the treatment of this disease is long and involves a mix of at least four different antibiotics that frequently lead to abandonment, favoring the surge of drug-resistant mycobacteria (MDR-TB), whose treatment becomes more aggressive, being longer and more toxic. Thus, the search for novel strategies for treatment that improves time or efficiency is of relevance. In this work, we used a murine model of pulmonary TB produced by the MDR-TB strain to test the efficiency of gene therapy with adenoviral vectors codifying TNF (AdTNF), a pro-inflammatory cytokine that has protective functions in TB by inducing apoptosis, granuloma formation and expression of other Th1-like cytokines. When compared to the control group that received an adenoviral vector that codifies for the green fluorescent protein (AdGFP), a single dose of AdTNF at the chronic active stage of the disease produced total survival, decreasing bacterial load and tissue damage (pneumonia), which correlated with an increase in cells expressing IFN-\u03b3, iNOS and TNF in pneumonic areas and larger granulomas that efficiently contain and eliminate mycobacteria. Second-line antibiotic treatment against MDR-TB plus AdTNF gene therapy reduced bacterial load faster within a week of treatment compared to empty vector plus antibiotics or antibiotics alone, suggesting that AdTNF is a new potential type of treatment against MDR-TB that can shorten second-line chemotherapy but which requires further experimentation in other animal models (non-human primates) that develop a more similar disease to human pulmonary TB.<\/jats:p>","DOI":"10.3390\/microorganisms11122934","type":"journal-article","created":{"date-parts":[[2023,12,7]],"date-time":"2023-12-07T03:35:31Z","timestamp":1701920131000},"page":"2934","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Adenoviral Vector Codifying for TNF as a Co-Adjuvant Therapy against Multi-Drug-Resistant Tuberculosis"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3251-2479","authenticated-orcid":false,"given":"Sujhey","family":"Hern\u00e1ndez-Baz\u00e1n","sequence":"first","affiliation":[{"name":"Secci\u00f3n de Patolog\u00eda Experimental, Departamento de Patolog\u00eda, Instituto Nacional de Ciencias M\u00e9dicas y Nutrici\u00f3n Salvador Zubir\u00e1n, Mexico City 14080, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dulce","family":"Mata-Espinosa","sequence":"additional","affiliation":[{"name":"Secci\u00f3n de Patolog\u00eda Experimental, Departamento de Patolog\u00eda, Instituto Nacional de Ciencias M\u00e9dicas y Nutrici\u00f3n Salvador Zubir\u00e1n, Mexico City 14080, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9010-4625","authenticated-orcid":false,"given":"Octavio","family":"Ramos-Espinosa","sequence":"additional","affiliation":[{"name":"Secci\u00f3n de Patolog\u00eda Experimental, Departamento de Patolog\u00eda, Instituto Nacional de Ciencias M\u00e9dicas y Nutrici\u00f3n Salvador Zubir\u00e1n, Mexico City 14080, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vasti","family":"Lozano-Ordaz","sequence":"additional","affiliation":[{"name":"Secci\u00f3n de Patolog\u00eda Experimental, Departamento de Patolog\u00eda, Instituto Nacional de Ciencias M\u00e9dicas y Nutrici\u00f3n Salvador Zubir\u00e1n, Mexico City 14080, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5134-5573","authenticated-orcid":false,"given":"Jorge","family":"Barrios-Pay\u00e1n","sequence":"additional","affiliation":[{"name":"Secci\u00f3n de Patolog\u00eda Experimental, Departamento de Patolog\u00eda, Instituto Nacional de Ciencias M\u00e9dicas y Nutrici\u00f3n Salvador Zubir\u00e1n, Mexico City 14080, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fernando","family":"L\u00f3pez-Casillas","sequence":"additional","affiliation":[{"name":"Departamento de Biolog\u00eda Celular, Instituto de Fisiolog\u00eda Celular, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Mexico City 14080, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rogelio","family":"Hern\u00e1ndez-Pando","sequence":"additional","affiliation":[{"name":"Secci\u00f3n de Patolog\u00eda Experimental, Departamento de Patolog\u00eda, Instituto Nacional de Ciencias M\u00e9dicas y Nutrici\u00f3n Salvador Zubir\u00e1n, Mexico City 14080, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,7]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2022). Global Tuberculosis Report, World Health Organization."},{"key":"ref_2","first-page":"729","article-title":"The Diagnosis and Treatment of Tuberculosis","volume":"116","author":"Rademacher","year":"2019","journal-title":"Dtsch. Arztebl. Int."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1146\/annurev-immunol-032712-095939","article-title":"The Immune Response in Tuberculosis","volume":"31","author":"Redford","year":"2013","journal-title":"Annu. Rev. Immunol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.cyto.2016.08.027","article-title":"TNFR Signalling and Its Clinical Implications","volume":"101","author":"Tseng","year":"2018","journal-title":"Cytokine"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2757","DOI":"10.1242\/jcs.115.13.2757","article-title":"Apoptotic Crosstalk of TNF Receptors: TNF-R2-Induces Depletion of TRAF2 and IAP Proteins and Accelerates TNF-R1-Dependent Activation of Caspase-8","volume":"115","author":"Henkler","year":"2002","journal-title":"J. Cell Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e2375","DOI":"10.1038\/cddis.2016.285","article-title":"Activation of TNFR2 Sensitizes Macrophages for TNFR1-Mediated Necroptosis","volume":"7","author":"Siegmund","year":"2016","journal-title":"Cell Death Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1038\/nrrheum.2015.169","article-title":"TNF Biology, Pathogenic Mechanisms and Emerging Therapeutic Strategies","volume":"12","author":"Kalliolias","year":"2016","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.molimm.2020.11.020","article-title":"Mycobacterium tuberculosis EsxL Induces TNF-\u03b1 Secretion through Activation of TLR2 Dependent MAPK and NF-\u039aB Pathways","volume":"130","author":"Pattanaik","year":"2021","journal-title":"Mol. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1016\/1074-7613(95)90001-2","article-title":"Tumor Necrosis Factor-Alfa Is Required in the Protective Immune Response Against Mycobacterium tuberculosis in Mice","volume":"2","author":"Flynn","year":"1995","journal-title":"Immunity"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1098","DOI":"10.1056\/NEJMoa011110","article-title":"Tuberculosis Associated with Infliximab, a Tumor Necrosis Factor Alpha-Neutralizing Agent","volume":"345","author":"Keane","year":"2001","journal-title":"N. Engl. J. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1365-2249.2010.04146.x","article-title":"How Tumour Necrosis Factor Blockers Interfere with Tuberculosis Immunity","volume":"161","author":"Harris","year":"2010","journal-title":"Clin. Exp. Immunol."},{"key":"ref_12","first-page":"1491","article-title":"Risk of Cancer, Tuberculosis and Serious Infections in Patients with Ankylosing Spondylitis, Psoriatic Arthritis, and Psoriasis Treated with IL-17 and TNF-\u03b1 Inhibitors: A Nationwide Nested Case-Control Analysis","volume":"41","author":"Kim","year":"2023","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"6122","DOI":"10.4049\/jimmunol.162.10.6122","article-title":"TNF-\u03b1 and IL-10 Modulate the Induction of Apoptosis by Virulent Mycobacterium tuberculosis in Murine Macrophages","volume":"162","author":"Rojas","year":"1999","journal-title":"J. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"ftw075","DOI":"10.1093\/femspd\/ftw075","article-title":"Gene Therapy Based in Antimicrobial Peptides and Proinflammatory Cytokine Prevents Reactivation of Experimental Latent Tuberculosis","volume":"74","author":"Carretero","year":"2016","journal-title":"Pathog. Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1038\/mt.2008.69","article-title":"Therapeutic Effect of Recombinant Adenovirus Encoding Interferon-Gamma in a Murine Model of Progressive Pulmonary Tuberculosis","volume":"16","author":"Rosales","year":"2008","journal-title":"Mol. Ther."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1089\/hum.2022.030","article-title":"Immune Regulatory Effect of Osteopontin Gene Therapy in a Murine Model of Multidrug Resistant Pulmonary Tuberculosis","volume":"33","author":"Pando","year":"2022","journal-title":"Hum. Gene Ther."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1111\/j.1574-695X.1995.tb00176.x","article-title":"Adrenal Changes in Murine Pulmonary Tuberculosis; a Clue to Pathogenesis?","volume":"12","author":"Orozco","year":"1995","journal-title":"FEMS Immunol. Med. Microbiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1007\/s12033-007-0021-5","article-title":"Adenoviral Vectors for Gene Therapy","volume":"36","author":"Douglas","year":"2007","journal-title":"Mol. Biotechnol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1038\/mi.2011.13","article-title":"Role of Innate Cytokines in Mycobacterial Infection","volume":"4","author":"Cooper","year":"2011","journal-title":"Mucosal Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Liebenberg, D., Gordhan, B.G., and Kana, B.D. (2022). Drug Resistant Tuberculosis: Implications for Transmission, Diagnosis, and Disease Management. Front. Cell. Infect. Microbiol., 12.","DOI":"10.3389\/fcimb.2022.943545"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2064","DOI":"10.1080\/21645515.2016.1165908","article-title":"Adenoviral Vector-Based Strategies against Infectious Disease and Cancer","volume":"12","author":"Zhang","year":"2016","journal-title":"Hum. Vaccines Immunother."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1016\/j.ymthe.2004.07.013","article-title":"Adenoviruses as Vaccine Vectors","volume":"10","author":"Tatsis","year":"2004","journal-title":"Mol. Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"982","DOI":"10.1089\/hum.2017.164","article-title":"The Future Looks Brighter After 25 Years of Retinal Gene Therapy","volume":"28","author":"Auricchio","year":"2017","journal-title":"Hum. Gene Ther."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Ricobaraza, A., Gonzalez-Aparicio, M., Mora-Jimenez, L., Lumbreras, S., and Hernandez-Alcoceba, R. (2020). High-Capacity Adenoviral Vectors: Expanding the Scope of Gene Therapy. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21103643"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2573","DOI":"10.1099\/0022-1317-81-11-2573","article-title":"Update on Adenovirus and Its Vectors","volume":"81","author":"Russell","year":"2000","journal-title":"J. Gen. Virol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1189\/jlb.0603252","article-title":"Interferon-\u03b3: An Overview of Signals, Mechanisms and Functions","volume":"75","author":"Schroder","year":"2004","journal-title":"J. Leukoc. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1515\/bmc-2018-0007","article-title":"Interferon-Gamma (IFN-\u03b3): Exploring Its Implications in Infectious Diseases","volume":"9","author":"Kak","year":"2018","journal-title":"Biomol. Concepts"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"16076","DOI":"10.1038\/nrdp.2016.76","article-title":"Tuberculosis","volume":"2","author":"Pai","year":"2016","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_29","first-page":"720","article-title":"Levels of Interferon-\u03b3 and Interleukin-2 Receptor-\u03b1 for Bronchoalveolar Lavage Fluid and Serum Were Correlated with Clinical Grade and Treatment of Pulmonary Tuberculosis","volume":"6","author":"Tsao","year":"2002","journal-title":"Int. J. Tuberc. Lung Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1086\/344903","article-title":"Serum Cytokine Concentrations Do Not Parallel Mycobacterium tuberculosis\u2014Induced Cytokine Production in Patients with Tuberculosis","volume":"36","author":"Vankayalapati","year":"2003","journal-title":"Clin. Infect. Dis."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"870","DOI":"10.1086\/511277","article-title":"Immunosuppression during Active Tuberculosis Is Characterized by Decreased Interferon- Gamma Production and CD25 Expression with Elevated Forkhead Box P3, Transforming Growth Factor- Beta, and Interleukin-4 MRNA Levels","volume":"195","author":"Roberts","year":"2007","journal-title":"J. Infect. Dis."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1111\/j.1574-695X.1998.tb01207.x","article-title":"Th2 Biased Immune Response in Cases with Active Mycobacterium tuberculosis Infection and Tuberculin Anergy","volume":"22","author":"Szereday","year":"1998","journal-title":"FEMS Immunol. Med. Microbiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1002\/med.21599","article-title":"Inducible Nitric Oxide Synthase: Regulation, Structure, and Inhibition","volume":"40","author":"Cinelli","year":"2020","journal-title":"Med. Res. Rev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"35887","DOI":"10.1074\/jbc.M112.365171","article-title":"A Role for CGMP in Inducible Nitric-Oxide Synthase (INOS)-Induced Tumor Necrosis Factor (TNF) \u03b1-Converting Enzyme (TACE\/ADAM17) Activation, Translocation, and TNF Receptor 1 (TNFR1) Shedding in Hepatocytes","volume":"287","author":"Chanthaphavong","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/S0027-5107(99)00006-8","article-title":"The Chemistry of DNA Damage from Nitric Oxide and Peroxynitrite","volume":"424","author":"Burney","year":"1999","journal-title":"Mutat. Res. Mol. Mech. Mutagen."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"7711","DOI":"10.1128\/IAI.69.12.7711-7717.2001","article-title":"The Inducible Nitric Oxide Synthase Locus Confers Protection against Aerogenic Challenge of Both Clinical and Laboratory Strains of Mycobacterium tuberculosis in Mice","volume":"69","author":"Scanga","year":"2001","journal-title":"Infect. Immun."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1038\/nri3211","article-title":"Revisiting the Role of the Granuloma in Tuberculosis","volume":"12","author":"Ramakrishnan","year":"2012","journal-title":"Nat. Rev. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"442","DOI":"10.3349\/ymj.2014.55.2.442","article-title":"Incidences of Serious Infections and Tuberculosis among Patients Receiving Anti-Tumor Necrosis Factor-\u03b1 Therapy","volume":"55","author":"Yoo","year":"2014","journal-title":"Yonsei Med. J."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"483","DOI":"10.4049\/jimmunol.165.1.483","article-title":"Lethal Granuloma Disintegration in Mycobacteria-Infected TNFRp55\u2212\/\u2212 Mice Is Dependent on T Cells and IL-12","volume":"165","author":"Ehlers","year":"2000","journal-title":"J. Immunol."},{"key":"ref_40","first-page":"26","article-title":"Correlation between the Kinetics of Th1, Th2 Cells and Pathology in a Murine Model of Experimental Pulmonary Tuberculosis","volume":"89","author":"Orozcoe","year":"1996","journal-title":"Immunology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"4682","DOI":"10.1016\/j.cell.2022.10.025","article-title":"Immune Cell Interactions in Tuberculosis","volume":"185","author":"Flynn","year":"2022","journal-title":"Cell"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1128\/microbiolspec.GPP3-0022-2018","article-title":"Immunology of Mycobacterium tuberculosis Infections","volume":"7","author":"Sia","year":"2019","journal-title":"Microbiol. Spectr."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"eabh2841","DOI":"10.1126\/science.abh2841","article-title":"TNF Induces Pathogenic Mitochondrial ROS in Tuberculosis through Reverse Electron Transport","volume":"376","author":"Roca","year":"2022","journal-title":"Science"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1007\/s13318-019-00604-5","article-title":"A Review of Clinical Pharmacokinetic and Pharmacodynamic Relationships and Clinical Implications for Drugs Used to Treat Multi-Drug Resistant Tuberculosis","volume":"45","author":"Wilby","year":"2020","journal-title":"Eur. J. Drug Metab. Pharmacokinet."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1111\/cei.12015","article-title":"Immunotherapeutic Effects of Recombinant Adenovirus Encoding Granulocyte-Macrophage Colony-Stimulating Factor in Experimental Pulmonary Tuberculosis","volume":"171","author":"Xing","year":"2013","journal-title":"Clin. Exp. Immunol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1002\/JLB.4MA0920-627R","article-title":"Immunotherapeutic Effect of Adenovirus Encoding Antimicrobial Peptides in Experimental Pulmonary Tuberculosis","volume":"110","author":"Carretero","year":"2021","journal-title":"J. Leukoc. Biol."}],"container-title":["Microorganisms"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-2607\/11\/12\/2934\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:34:25Z","timestamp":1760132065000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-2607\/11\/12\/2934"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,7]]},"references-count":46,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["microorganisms11122934"],"URL":"https:\/\/doi.org\/10.3390\/microorganisms11122934","relation":{},"ISSN":["2076-2607"],"issn-type":[{"type":"electronic","value":"2076-2607"}],"subject":[],"published":{"date-parts":[[2023,12,7]]}}}