Fitness costs of Mycobacterium tuberculosis resistant to rifampicin is compensated by rapid Th2 polarization mediated by early and high IL-4 production during mice infection
Abstract It was a general belief that drug resistance in Mycobacterium tuberculosis (Mtb) was associated with lesser virulence, particularly rifampicin resistance, which is usually produced by mutations in the RNA polymerase Beta subunit (RpoB). Interestingly, this kind of bacterial mutations affect...
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Nature Portfolio
2025-01-01
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| Online Access: | https://doi.org/10.1038/s41598-024-81446-3 |
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| author | Ma. Fernanda Arce-Aceves Roberto Espinosa-Neira Dulce A. Mata-Espinosa Jorge A. Barrios-Payan Hugo G. Castelán-Sánchez Sofía L. Alcaraz-Estrada Mauricio Castañón-Arreola Rogelio Hernández-Pando |
| author_facet | Ma. Fernanda Arce-Aceves Roberto Espinosa-Neira Dulce A. Mata-Espinosa Jorge A. Barrios-Payan Hugo G. Castelán-Sánchez Sofía L. Alcaraz-Estrada Mauricio Castañón-Arreola Rogelio Hernández-Pando |
| author_sort | Ma. Fernanda Arce-Aceves |
| collection | DOAJ |
| description | Abstract It was a general belief that drug resistance in Mycobacterium tuberculosis (Mtb) was associated with lesser virulence, particularly rifampicin resistance, which is usually produced by mutations in the RNA polymerase Beta subunit (RpoB). Interestingly, this kind of bacterial mutations affect gene transcription with significant effects on bacterial physiology and metabolism, affecting also the bacterial antigenic constitution that in consequence can produce diverse immune responses and disease outcome. In the present study, we show the results of the Mtb clinical isolate A96, which is resistant to rifampicin and when used to infect BALB/c mice showed hypervirulence, apparently by rapidly polarization of the Th2 immune response through early and high production of IL-4. The 2D-PAGE analysis of the secretome of Mtb A96 showed 204 spots, and by immunoproteome, seven proteins that were differentially recognized with the sera of infected mice on day 28 were identified by LC-MS/MS. The proteins correspond to surface antigens, virulence factors, and energy metabolism enzymes. Some of them are immunodominant antigens, such as LpqH lipoprotein that induces IL-4 secretion in cell suspensions from the lung and spleen of mice infected with Mtb A96 at 28 days postinfection, suggesting that LpqH could be one of the main antigens involved in the Th2 polarization. The reduction of Mtb A96 hypervirulence in IL-4Rα−/− BALB/c mice highlights the importance of IL-4 induction and Th2 response polarization and the immunopathological response. Thus, high and rapid bias to Th2 response is a mechanism of Mtb virulence, which could be mediated by rifampicin-resistant Mtb isolates, probably by high production and secretion of specific antigens. |
| format | Article |
| id | doaj-art-3b718c6e41c84f1a843e5c2215ac70fd |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj-art-3b718c6e41c84f1a843e5c2215ac70fd2025-01-26T12:32:01ZengNature PortfolioScientific Reports2045-23222025-01-0115111510.1038/s41598-024-81446-3Fitness costs of Mycobacterium tuberculosis resistant to rifampicin is compensated by rapid Th2 polarization mediated by early and high IL-4 production during mice infectionMa. Fernanda Arce-Aceves0Roberto Espinosa-Neira1Dulce A. Mata-Espinosa2Jorge A. Barrios-Payan3Hugo G. Castelán-Sánchez4Sofía L. Alcaraz-Estrada5Mauricio Castañón-Arreola6Rogelio Hernández-Pando7Experimental Pathology Department, National Institute of Medical Sciences and Nutrition Salvador ZubiranPosgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad de MéxicoExperimental Pathology Department, National Institute of Medical Sciences and Nutrition Salvador ZubiranExperimental Pathology Department, National Institute of Medical Sciences and Nutrition Salvador ZubiranDepartment of Pathology and Laboratory Medicine, Western UniversityVirological Analysis and Reference Unit, Institute for Social Security and Services for State Workers, National Medical Center “20 de Noviembre”Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad de MéxicoExperimental Pathology Department, National Institute of Medical Sciences and Nutrition Salvador ZubiranAbstract It was a general belief that drug resistance in Mycobacterium tuberculosis (Mtb) was associated with lesser virulence, particularly rifampicin resistance, which is usually produced by mutations in the RNA polymerase Beta subunit (RpoB). Interestingly, this kind of bacterial mutations affect gene transcription with significant effects on bacterial physiology and metabolism, affecting also the bacterial antigenic constitution that in consequence can produce diverse immune responses and disease outcome. In the present study, we show the results of the Mtb clinical isolate A96, which is resistant to rifampicin and when used to infect BALB/c mice showed hypervirulence, apparently by rapidly polarization of the Th2 immune response through early and high production of IL-4. The 2D-PAGE analysis of the secretome of Mtb A96 showed 204 spots, and by immunoproteome, seven proteins that were differentially recognized with the sera of infected mice on day 28 were identified by LC-MS/MS. The proteins correspond to surface antigens, virulence factors, and energy metabolism enzymes. Some of them are immunodominant antigens, such as LpqH lipoprotein that induces IL-4 secretion in cell suspensions from the lung and spleen of mice infected with Mtb A96 at 28 days postinfection, suggesting that LpqH could be one of the main antigens involved in the Th2 polarization. The reduction of Mtb A96 hypervirulence in IL-4Rα−/− BALB/c mice highlights the importance of IL-4 induction and Th2 response polarization and the immunopathological response. Thus, high and rapid bias to Th2 response is a mechanism of Mtb virulence, which could be mediated by rifampicin-resistant Mtb isolates, probably by high production and secretion of specific antigens.https://doi.org/10.1038/s41598-024-81446-3TuberculosisInterleukin-4RIF-resistanceLipoprotein LpqHHypervirulent |
| spellingShingle | Ma. Fernanda Arce-Aceves Roberto Espinosa-Neira Dulce A. Mata-Espinosa Jorge A. Barrios-Payan Hugo G. Castelán-Sánchez Sofía L. Alcaraz-Estrada Mauricio Castañón-Arreola Rogelio Hernández-Pando Fitness costs of Mycobacterium tuberculosis resistant to rifampicin is compensated by rapid Th2 polarization mediated by early and high IL-4 production during mice infection Scientific Reports Tuberculosis Interleukin-4 RIF-resistance Lipoprotein LpqH Hypervirulent |
| title | Fitness costs of Mycobacterium tuberculosis resistant to rifampicin is compensated by rapid Th2 polarization mediated by early and high IL-4 production during mice infection |
| title_full | Fitness costs of Mycobacterium tuberculosis resistant to rifampicin is compensated by rapid Th2 polarization mediated by early and high IL-4 production during mice infection |
| title_fullStr | Fitness costs of Mycobacterium tuberculosis resistant to rifampicin is compensated by rapid Th2 polarization mediated by early and high IL-4 production during mice infection |
| title_full_unstemmed | Fitness costs of Mycobacterium tuberculosis resistant to rifampicin is compensated by rapid Th2 polarization mediated by early and high IL-4 production during mice infection |
| title_short | Fitness costs of Mycobacterium tuberculosis resistant to rifampicin is compensated by rapid Th2 polarization mediated by early and high IL-4 production during mice infection |
| title_sort | fitness costs of mycobacterium tuberculosis resistant to rifampicin is compensated by rapid th2 polarization mediated by early and high il 4 production during mice infection |
| topic | Tuberculosis Interleukin-4 RIF-resistance Lipoprotein LpqH Hypervirulent |
| url | https://doi.org/10.1038/s41598-024-81446-3 |
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