{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T12:06:01Z","timestamp":1784030761887,"version":"3.55.0"},"reference-count":44,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2024,4,13]],"date-time":"2024-04-13T00:00:00Z","timestamp":1712966400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Instituto Nacional de Enfermedades Respiratorias Ismael Cos\u00edo Villegas (INER)","award":["B09-18"],"award-info":[{"award-number":["B09-18"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Bactericidal permeability-increasing protein (BPI) is a multifunctional cationic protein produced by neutrophils, eosinophils, fibroblasts, and macrophages with antibacterial anti-inflammatory properties. In the context of Gram-negative infection, BPI kills bacteria, neutralizes the endotoxic activity of lipopolysaccharides (LPSs), and, thus, avoids immune hyperactivation. Interestingly, BPI increases in patients with Gram-positive meningitis, interacts with lipopeptides and lipoteichoic acids of Gram-positive bacteria, and significantly enhances the immune response in peripheral blood mononuclear cells. We evaluated the antimycobacterial and immunoregulatory properties of BPI in human macrophages infected with Mycobacterium tuberculosis. Our results showed that recombinant BPI entered macrophages, significantly reduced the intracellular growth of M. tuberculosis, and inhibited the production of the proinflammatory cytokine tumor necrosis factor-alpha (TNF-\u03b1). Furthermore, BPI decreased bacterial growth directly in vitro. These data suggest that BPI has direct and indirect bactericidal effects inhibiting bacterial growth and potentiating the immune response in human macrophages and support that this new protein\u2019s broad-spectrum antibacterial activity has the potential for fighting tuberculosis.<\/jats:p>","DOI":"10.3390\/biom14040475","type":"journal-article","created":{"date-parts":[[2024,4,15]],"date-time":"2024-04-15T11:53:53Z","timestamp":1713182033000},"page":"475","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Bactericidal Permeability-Increasing Protein (BPI) Inhibits Mycobacterium tuberculosis Growth"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7491-1910","authenticated-orcid":false,"given":"Silvia","family":"Guzm\u00e1n-Beltr\u00e1n","sequence":"first","affiliation":[{"name":"Department of Microbiology, National Institute for Respiratory Diseases Ismael Cosio Villegas, Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9036-004X","authenticated-orcid":false,"given":"Esmeralda","family":"Ju\u00e1rez","sequence":"additional","affiliation":[{"name":"Department of Microbiology, National Institute for Respiratory Diseases Ismael Cosio Villegas, Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brenda L.","family":"Cruz-Mu\u00f1oz","sequence":"additional","affiliation":[{"name":"Department of Microbiology, National Institute for Respiratory Diseases Ismael Cosio Villegas, Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cesar A.","family":"P\u00e1ez-Cisneros","sequence":"additional","affiliation":[{"name":"Department of Microbiology, National Institute for Respiratory Diseases Ismael Cosio Villegas, Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"Sarabia","sequence":"additional","affiliation":[{"name":"Department of Microbiology, National Institute for Respiratory Diseases Ismael Cosio Villegas, Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7066-6188","authenticated-orcid":false,"given":"Yolanda","family":"Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Department of Microbiology, National Institute for Respiratory Diseases Ismael Cosio Villegas, Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"455","DOI":"10.3389\/fimmu.2016.00455","article-title":"Of Men Not Mice: Bactericidal\/Permeability-Increasing Protein Expressed in Human Macrophages Acts as a Phagocytic Receptor and Modulates Entry and Replication of Gram-Negative Bacteria","volume":"7","author":"Balakrishnan","year":"2016","journal-title":"Front. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1172\/JCI107915","article-title":"Partial Characterization and Purification of a Rabbit Granulocyte Factor That Increases Permeability of Escherichia Coli","volume":"55","author":"Weiss","year":"1975","journal-title":"J. Clin. Investig."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"10973","DOI":"10.1073\/pnas.94.20.10973","article-title":"An Opsonic Function of the Neutrophil Bactericidal\/Permeability-Increasing Protein Depends on Both Its N- and C-Terminal Domains","volume":"94","author":"Iovine","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/S0171-2985(11)80354-2","article-title":"The Bactericidal\/Permeability-Increasing Protein (BPI), a Potent Element in Host-Defense Against Gram-Negative Bacteria and Lipopolysaccharide","volume":"187","author":"Elsbach","year":"1993","journal-title":"Immunobiology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"659523","DOI":"10.3389\/fimmu.2021.659523","article-title":"Bactericidal\/Permeability-Increasing Protein Preeminently Mediates Clearance of Pseudomonas Aeruginosa In Vivo via CD18-Dependent Phagocytosis","volume":"12","author":"Theprungsirikul","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/S0952-7915(98)80030-7","article-title":"Role of the Bactericidal\/Permeability-Increasing Protein in Host Defence","volume":"10","author":"Elsbach","year":"1998","journal-title":"Curr. Opin. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1177\/1753425912465098","article-title":"Bactericidal\/Permeability Increasing Protein: A Multifaceted Protein with Functions beyond LPS Neutralization","volume":"19","author":"Balakrishnan","year":"2013","journal-title":"Innate Immun."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1861","DOI":"10.1126\/science.276.5320.1861","article-title":"Crystal Structure of Human BPI and Two Bound Phospholipids at 2.4 Angstrom Resolution","volume":"276","author":"Beamer","year":"1997","journal-title":"Science"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1016\/j.bbalip.2016.01.016","article-title":"The TULIP Superfamily of Eukaryotic Lipid-Binding Proteins as a Mediator of Lipid Sensing and Transport","volume":"1861","author":"Alva","year":"2016","journal-title":"Biochim. Biophys. Acta Mol. Cell Biol. Lipids"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Ederer, K.U., Holzinger, J.M., Maier, K.T., Zeller, L., Werner, M., Toelge, M., Gessner, A., and B\u00fclow, S. (2022). A Polymorphism of Bactericidal\/Permeability-Increasing Protein Affects Its Neutralization Efficiency towards Lipopolysaccharide. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031324"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1084\/jem.174.3.649","article-title":"Endotoxin-Neutralizing Properties of the 25 KD N-Terminal Fragment and a Newly Isolated 30 KD C-Terminal Fragment of the 55-60 KD Bactericidal\/Permeability-Increasing Protein of Human Neutrophils","volume":"174","author":"Ooi","year":"1991","journal-title":"J. Exp. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"24309","DOI":"10.1074\/jbc.273.38.24309","article-title":"Phosphatidylinositides Bind to Plasma Membrane CD14 and Can Prevent Monocyte Activation by Bacterial Lipopolysaccharide","volume":"273","author":"Wang","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"10186","DOI":"10.1074\/jbc.M117.796631","article-title":"Lipopolysaccharide (LPS)-Binding Protein Stimulates CD14-Dependent Toll-like Receptor 4 Internalization and LPS-Induced TBK1-IKK\u03b1-IRF3 Axis Activation","volume":"293","author":"Tsukamoto","year":"2018","journal-title":"J. Biol. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1128\/iai.62.4.1185-1191.1994","article-title":"Competition between RBPI23, a Recombinant Fragment of Bactericidal\/Permeability-Increasing Protein, and Lipopolysaccharide (LPS)-Binding Protein for Binding to LPS and Gram-Negative Bacteria","volume":"62","author":"Meszaros","year":"1994","journal-title":"Infect. Immun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2664","DOI":"10.1016\/S0021-9258(17)40872-6","article-title":"Purification and Characterization of a Potent Bactericidal and Membrane Active Protein from the Granules of Human Polymorphonuclear Leukocytes","volume":"253","author":"Weiss","year":"1978","journal-title":"J. Biol. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"86369","DOI":"10.7554\/eLife.86369","article-title":"Scorpionfish BPI Is Highly Active against Multiple Drug-Resistant Pseudomonas Aeruginosa Isolates from People with Cystic Fibrosis","volume":"12","author":"Holzinger","year":"2023","journal-title":"Elife"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.vetmic.2007.05.004","article-title":"A Peptide Derived from Human Bactericidal\/Permeability-Increasing Protein (BPI) Exerts Bactericidal Activity against Gram-Negative Bacterial Isolates Obtained from Clinical Cases of Bovine Mastitis","volume":"125","author":"Chockalingam","year":"2007","journal-title":"Vet. Microbiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2768","DOI":"10.3389\/fimmu.2018.02768","article-title":"Bactericidal\/Permeability-Increasing Protein Is an Enhancer of Bacterial Lipoprotein Recognition","volume":"9","author":"Zeller","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1128\/IAI.01089-06","article-title":"Recombinant Bactericidal\/Permeability-Increasing Protein RBPI21 Protects against Pneumococcal Disease","volume":"75","author":"Srivastava","year":"2007","journal-title":"Infect. Immun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1016\/j.chest.2022.01.014","article-title":"Global Impact of Respiratory Disease: What Can We Do, Together, to Make a Difference?","volume":"161","author":"Levine","year":"2022","journal-title":"Chest"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"100105","DOI":"10.1016\/j.jtauto.2021.100105","article-title":"Killing Three Birds with One BPI: Bactericidal, Opsonic, and Anti-Inflammatory Functions","volume":"4","author":"Theprungsirikul","year":"2021","journal-title":"J. Transl. Autoimmun."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Alsayed, S.S.R., and Gunosewoyo, H. (2023). Tuberculosis: Pathogenesis, Current Treatment Regimens and New Drug Targets. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24065202"},{"key":"ref_23","unstructured":"(2024, January 10). World Health Organization. Available online: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/tuberculosis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"105694","DOI":"10.1016\/j.intimp.2019.105694","article-title":"Resolvin D1 (RvD1) and Maresin 1 (Mar1) Contribute to Human Macrophage Control of M. Tuberculosis Infection While Resolving Inflammation","volume":"74","author":"Ruiz","year":"2019","journal-title":"Int. Immunopharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Carroll, P., Schreuder, L.J., Muwanguzi-Karugaba, J., Wiles, S., Robertson, B.D., Ripoll, J., Ward, T.H., Bancroft, G.J., Schaible, U.E., and Parish, T. (2010). Sensitive Detection of Gene Expression in Mycobacteria under Replicating and Non-Replicating Conditions Using Optimized Far-Red Reporters. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0009823"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.intimp.2015.12.027","article-title":"Nordihydroguaiaretic Acid (NDGA) and \u03b1-Mangostin Inhibit the Growth of Mycobacterium Tuberculosis by Inducing Autophagy","volume":"31","author":"Torres","year":"2016","journal-title":"Int. Immunopharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: An Open-Source Platform for Biological-Image Analysis","volume":"9","author":"Schindelin","year":"2012","journal-title":"Nat. Methods"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1488","DOI":"10.1016\/j.cmi.2020.07.036","article-title":"Antimicrobial Susceptibility Testing of Mycobacterium Tuberculosis Complex Isolates\u2014The EUCAST Broth Microdilution Reference Method for MIC Determination","volume":"26","author":"Werngren","year":"2020","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1164\/rccm.200503-411OC","article-title":"Mycobacterium Tuberculosis Growth Control by Lung Macrophages and CD8 Cells from Patient Contacts","volume":"173","author":"Carranza","year":"2006","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/j.cell.2013.03.022","article-title":"TNF Dually Mediates Resistance and Susceptibility to Mycobacteria via Mitochondrial Reactive Oxygen Species","volume":"153","author":"Roca","year":"2013","journal-title":"Cell"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Herrera, M.T., Guzm\u00e1n-Beltr\u00e1n, S., Bobadilla, K., Santos-Mendoza, T., Flores-Valdez, M.A., Guti\u00e9rrez-Gonz\u00e1lez, L.H., and Gonz\u00e1lez, Y. (2022). Human Pulmonary Tuberculosis: Understanding the Immune Response in the Bronchoalveolar System. Biomolecules, 12.","DOI":"10.3390\/biom12081148"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1001\/archsurg.1996.01430140090023","article-title":"Mononuclear Cell Line THP-1 Internalizes Bactericidal\/Permeability-Increasing Protein by a Non-Receptor-Mediated Mechanism Consistent with Pinocytosis","volume":"131","author":"Burnett","year":"1996","journal-title":"Arch. Surg."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Buccini, D.F., Cardoso, M.H., and Franco, O.L. (2021). Antimicrobial Peptides and Cell-Penetrating Peptides for Treating Intracellular Bacterial Infections. Front. Cell. Infect. Microbiol., 10.","DOI":"10.3389\/fcimb.2020.612931"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1182\/blood.V69.2.652.652","article-title":"Cellular and Subcellular Localization of the Bactericidal\/Permeability-Increasing Protein of Neutrophils","volume":"69","author":"Weiss","year":"1987","journal-title":"Blood"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1670","DOI":"10.3389\/fimmu.2019.01670","article-title":"Regulation of Pseudomonas Aeruginosa-Mediated Neutrophil Extracellular Traps","volume":"10","author":"Theprungsirikul","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.autrev.2006.08.005","article-title":"From Infection to Autoimmunity: A New Model for Induction of ANCA against the Bactericidal\/Permeability Increasing Protein (BPI)","volume":"6","author":"Schultz","year":"2007","journal-title":"Autoimmun. Rev."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4754","DOI":"10.1128\/iai.60.11.4754-4761.1992","article-title":"High-Affinity Binding of the Bactericidal\/Permeability-Increasing Protein and a Recombinant Amino-Terminal Fragment to the Lipid A Region of Lipopolysaccharide","volume":"60","author":"Parent","year":"1992","journal-title":"Infect. Immun."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"10311","DOI":"10.1021\/bi970177e","article-title":"Mechanisms of Action of Bactericidal\/Permeability-Increasing Protein BPI on Reconstituted Outer Membranes of Gram-Negative Bacteria","volume":"36","author":"Wiese","year":"1997","journal-title":"Biochemistry"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2314","DOI":"10.1128\/AAC.43.9.2314","article-title":"Bactericidal\/Permeability-Increasing Protein Inhibits Growth of a Strain of Acholeplasma Laidlawii and L Forms of the Gram-Positive Bacteria Staphylococcus Aureus and Streptococcus Pyogenes","volume":"43","author":"Horwitz","year":"1999","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Bian, Z.C., Cai, X.H., Tan, K.A., Wang, Y.D., Huang, Z., Kwan, K.Y., and Xu, P. (2023). Identification and Functional Analysis of ToBPI1\/LBP and ToBPI2\/LBP in Anti-Bacterial Infection of Trachinotus Ovatus. Genes, 14.","DOI":"10.3390\/genes14040826"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Pinkenburg, O., Meyer, T., Bannert, N., Norley, S., Bolte, K., Czudai-Matwich, V., Herold, S., Gessner, A., and Schnare, M. (2016). The Human Antimicrobial Protein Bactericidal\/Permeability-Increasing Protein (BPI) Inhibits the Infectivity of Influenza A Virus. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0156929"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1016\/1074-7613(94)90093-0","article-title":"CD14 Is a Pattern Recognition Receptor","volume":"1","author":"Pugin","year":"1994","journal-title":"Immunity"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Malefane, L., and Maarman, G. (2024). Post-Tuberculosis Lung Disease and Inflammatory Role Players: Can We Characterise the Myriad Inflammatory Pathways Involved to Gain a Better Understanding?. Chem. Biol. Interact., 387.","DOI":"10.1016\/j.cbi.2023.110817"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.cca.2007.07.005","article-title":"The Bactericidal\/Permeability-Increasing Protein (BPI) in Infection and Inflammatory Disease","volume":"384","author":"Schultz","year":"2007","journal-title":"Clin. Chim. Acta"}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/14\/4\/475\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:27:25Z","timestamp":1760106445000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/14\/4\/475"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,13]]},"references-count":44,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2024,4]]}},"alternative-id":["biom14040475"],"URL":"https:\/\/doi.org\/10.3390\/biom14040475","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4,13]]}}}