Prevention of tuberculosis in cynomolgus macaques by an attenuated Mycobacterium tuberculosis vaccine candidate
Abstract The need for novel vaccination strategies to control tuberculosis (TB) is underscored by the limited and variable efficacy of the currently licensed vaccine, Bacille Calmette-Guerin (BCG). SigH is critical for Mycobacterium tuberculosis (Mtb) to mitigate oxidative stress, and in its absence...
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Nature Portfolio
2025-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-57090-4 |
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| author | Dhiraj K. Singh Mushtaq Ahmed Sadia Akter Vinay Shivanna Allison N. Bucşan Abhishek Mishra Nadia A. Golden Peter J. Didier Lara A. Doyle Shannan Hall-Ursone Chad J. Roy Garima Arora Edward J. Dick Chinnaswamy Jagannath Smriti Mehra Shabaana A. Khader Deepak Kaushal |
| author_facet | Dhiraj K. Singh Mushtaq Ahmed Sadia Akter Vinay Shivanna Allison N. Bucşan Abhishek Mishra Nadia A. Golden Peter J. Didier Lara A. Doyle Shannan Hall-Ursone Chad J. Roy Garima Arora Edward J. Dick Chinnaswamy Jagannath Smriti Mehra Shabaana A. Khader Deepak Kaushal |
| author_sort | Dhiraj K. Singh |
| collection | DOAJ |
| description | Abstract The need for novel vaccination strategies to control tuberculosis (TB) is underscored by the limited and variable efficacy of the currently licensed vaccine, Bacille Calmette-Guerin (BCG). SigH is critical for Mycobacterium tuberculosis (Mtb) to mitigate oxidative stress, and in its absence Mtb is unable to scavenge host oxidative/nitrosative bursts. The MtbΔsigH (ΔsigH) isogenic mutant induces signatures of the innate immunity in macrophages and protects rhesus macaques from a lethal Mtb challenge. To understand the immune mechanisms of protection via mucosal vaccination with ΔsigH, we employed the resistant cynomolgus macaque model; and our results show that ΔsigH vaccination significantly protects against lethal Mtb challenge in this species. ΔsigH-vaccinated macaques are devoid of granulomas and instead generate inducible bronchus associated lymphoid structures, and robust antigen-specific CD4+ and CD8+ T cell responses, driven by a hyper-immune, trained immunity-like phenotype in host macrophages with enhanced antigen presentation. Correlates of protection in ΔsigH-vaccinated macaques include gene signatures of T cell activation, IFNG production, including IFN-responsive, activated T cells, concomitant with IFNG production, and suppression of IDO+ Type I IFN-responsive macrophage recruitment. Thus, ΔsigH is a promising lead candidate for further development as an antitubercular vaccine. |
| format | Article |
| id | doaj-art-bf3572d9fffb4913a74d91bcc0f4e714 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-bf3572d9fffb4913a74d91bcc0f4e7142025-08-20T02:16:49ZengNature PortfolioNature Communications2041-17232025-02-0116112010.1038/s41467-025-57090-4Prevention of tuberculosis in cynomolgus macaques by an attenuated Mycobacterium tuberculosis vaccine candidateDhiraj K. Singh0Mushtaq Ahmed1Sadia Akter2Vinay Shivanna3Allison N. Bucşan4Abhishek Mishra5Nadia A. Golden6Peter J. Didier7Lara A. Doyle8Shannan Hall-Ursone9Chad J. Roy10Garima Arora11Edward J. Dick12Chinnaswamy Jagannath13Smriti Mehra14Shabaana A. Khader15Deepak Kaushal16Southwest National Primate Research Center, Texas Biomedical Research InstituteDepartment of Microbiology, University of ChicagoDepartment of Microbiology, University of ChicagoSouthwest National Primate Research Center, Texas Biomedical Research InstituteTulane National Primate Research Center, Tulane University School of MedicineDepartment of Pathology and Genomic Medicine, Houston Methodist Research Institute, Weill-Cornell MedicineTulane National Primate Research Center, Tulane University School of MedicineTulane National Primate Research Center, Tulane University School of MedicineTulane National Primate Research Center, Tulane University School of MedicineSouthwest National Primate Research Center, Texas Biomedical Research InstituteTulane National Primate Research Center, Tulane University School of MedicineSouthwest National Primate Research Center, Texas Biomedical Research InstituteSouthwest National Primate Research Center, Texas Biomedical Research InstituteDepartment of Pathology and Genomic Medicine, Houston Methodist Research Institute, Weill-Cornell MedicineSouthwest National Primate Research Center, Texas Biomedical Research InstituteDepartment of Microbiology, University of ChicagoSouthwest National Primate Research Center, Texas Biomedical Research InstituteAbstract The need for novel vaccination strategies to control tuberculosis (TB) is underscored by the limited and variable efficacy of the currently licensed vaccine, Bacille Calmette-Guerin (BCG). SigH is critical for Mycobacterium tuberculosis (Mtb) to mitigate oxidative stress, and in its absence Mtb is unable to scavenge host oxidative/nitrosative bursts. The MtbΔsigH (ΔsigH) isogenic mutant induces signatures of the innate immunity in macrophages and protects rhesus macaques from a lethal Mtb challenge. To understand the immune mechanisms of protection via mucosal vaccination with ΔsigH, we employed the resistant cynomolgus macaque model; and our results show that ΔsigH vaccination significantly protects against lethal Mtb challenge in this species. ΔsigH-vaccinated macaques are devoid of granulomas and instead generate inducible bronchus associated lymphoid structures, and robust antigen-specific CD4+ and CD8+ T cell responses, driven by a hyper-immune, trained immunity-like phenotype in host macrophages with enhanced antigen presentation. Correlates of protection in ΔsigH-vaccinated macaques include gene signatures of T cell activation, IFNG production, including IFN-responsive, activated T cells, concomitant with IFNG production, and suppression of IDO+ Type I IFN-responsive macrophage recruitment. Thus, ΔsigH is a promising lead candidate for further development as an antitubercular vaccine.https://doi.org/10.1038/s41467-025-57090-4 |
| spellingShingle | Dhiraj K. Singh Mushtaq Ahmed Sadia Akter Vinay Shivanna Allison N. Bucşan Abhishek Mishra Nadia A. Golden Peter J. Didier Lara A. Doyle Shannan Hall-Ursone Chad J. Roy Garima Arora Edward J. Dick Chinnaswamy Jagannath Smriti Mehra Shabaana A. Khader Deepak Kaushal Prevention of tuberculosis in cynomolgus macaques by an attenuated Mycobacterium tuberculosis vaccine candidate Nature Communications |
| title | Prevention of tuberculosis in cynomolgus macaques by an attenuated Mycobacterium tuberculosis vaccine candidate |
| title_full | Prevention of tuberculosis in cynomolgus macaques by an attenuated Mycobacterium tuberculosis vaccine candidate |
| title_fullStr | Prevention of tuberculosis in cynomolgus macaques by an attenuated Mycobacterium tuberculosis vaccine candidate |
| title_full_unstemmed | Prevention of tuberculosis in cynomolgus macaques by an attenuated Mycobacterium tuberculosis vaccine candidate |
| title_short | Prevention of tuberculosis in cynomolgus macaques by an attenuated Mycobacterium tuberculosis vaccine candidate |
| title_sort | prevention of tuberculosis in cynomolgus macaques by an attenuated mycobacterium tuberculosis vaccine candidate |
| url | https://doi.org/10.1038/s41467-025-57090-4 |
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