Deletion of <italic toggle="yes">nuoG</italic> from the Vaccine Candidate <named-content content-type="genus-species">Mycobacterium bovis</named-content> BCG Δ<italic toggle="yes">ureC</italic>::<italic toggle="yes">hly</italic> Improves Protection against Tuberculosis
ABSTRACT The current tuberculosis (TB) vaccine, Mycobacterium bovis Bacillus Calmette-Guérin (BCG), provides insufficient protection against pulmonary TB. Previously, we generated a listeriolysin-expressing recombinant BCG strain, which to date has successfully completed phase I and phase IIa clinic...
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American Society for Microbiology
2016
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oai:doaj.org-article:a3795285567a431ba72958df4832df9e2021-11-15T15:50:17ZDeletion of <italic toggle="yes">nuoG</italic> from the Vaccine Candidate <named-content content-type="genus-species">Mycobacterium bovis</named-content> BCG Δ<italic toggle="yes">ureC</italic>::<italic toggle="yes">hly</italic> Improves Protection against Tuberculosis10.1128/mBio.00679-162150-7511https://doaj.org/article/a3795285567a431ba72958df4832df9e2016-07-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00679-16https://doaj.org/toc/2150-7511ABSTRACT The current tuberculosis (TB) vaccine, Mycobacterium bovis Bacillus Calmette-Guérin (BCG), provides insufficient protection against pulmonary TB. Previously, we generated a listeriolysin-expressing recombinant BCG strain, which to date has successfully completed phase I and phase IIa clinical trials. In an attempt to further improve efficacy, we deleted the antiapoptotic virulence gene nuoG, encoding NADH dehydrogenase 1 subunit G, from BCG ΔureC::hly. In vitro, deletion of nuoG unexpectedly led to strongly increased recruitment of the autophagosome marker LC3 to the engulfed vaccine, suggesting that nuoG also affects xenophagic pathways. In mice, BCG ΔureC::hly ΔnuoG vaccination was safer than BCG and improved protection over that of parental BCG ΔureC::hly, significantly reducing TB load in murine lungs, ameliorating pulmonary pathology, and enhancing immune responses. Transcriptome analysis of draining lymph nodes after vaccination with either BCG ΔureC::hly or BCG ΔureC::hly ΔnuoG demonstrated earlier and stronger induction of immune responses than that with BCG SSI and suggested upregulation of inflammasome activation and interferon-induced GTPases. In summary, BCG ΔureC::hly ΔnuoG is a promising next-generation TB vaccine candidate with excellent efficacy and safety. IMPORTANCE Autophagy and apoptosis are fundamental processes allowing cells to degrade their components or kill themselves, respectively. The immune system has adopted these mechanisms to eliminate intracellular pathogens. Residing in host cells, the causative agent of tuberculosis, Mycobacterium tuberculosis, has evolved strategies to set cellular programs of autophagy and apoptosis “on hold.” The mycobacterial gene nuoG was found to prevent host cell apoptosis. We have deleted nuoG in the live vaccine candidate BCG ΔureC::hly, which is in phase II clinical development, to leave cellular apoptosis “on go” upon immunization. In preclinical models, this strategy boosted immunity and improved protection from M. tuberculosis infection. Unexpectedly, we obtained compelling evidence that mycobacterial nuoG facilitates inhibition of autophagic pathways, suggesting a new role for this gene in the host-pathogen interplay in tuberculosis.Martin GengenbacherNatalie NieuwenhuizenAlexis VogelzangHaipeng LiuPeggy KaiserStefanie SchuererDoris LazarIna WagnerHans-Joachim MollenkopfStefan H. E. KaufmannAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 7, Iss 3 (2016) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Microbiology QR1-502 |
| spellingShingle |
Microbiology QR1-502 Martin Gengenbacher Natalie Nieuwenhuizen Alexis Vogelzang Haipeng Liu Peggy Kaiser Stefanie Schuerer Doris Lazar Ina Wagner Hans-Joachim Mollenkopf Stefan H. E. Kaufmann Deletion of <italic toggle="yes">nuoG</italic> from the Vaccine Candidate <named-content content-type="genus-species">Mycobacterium bovis</named-content> BCG Δ<italic toggle="yes">ureC</italic>::<italic toggle="yes">hly</italic> Improves Protection against Tuberculosis |
| description |
ABSTRACT The current tuberculosis (TB) vaccine, Mycobacterium bovis Bacillus Calmette-Guérin (BCG), provides insufficient protection against pulmonary TB. Previously, we generated a listeriolysin-expressing recombinant BCG strain, which to date has successfully completed phase I and phase IIa clinical trials. In an attempt to further improve efficacy, we deleted the antiapoptotic virulence gene nuoG, encoding NADH dehydrogenase 1 subunit G, from BCG ΔureC::hly. In vitro, deletion of nuoG unexpectedly led to strongly increased recruitment of the autophagosome marker LC3 to the engulfed vaccine, suggesting that nuoG also affects xenophagic pathways. In mice, BCG ΔureC::hly ΔnuoG vaccination was safer than BCG and improved protection over that of parental BCG ΔureC::hly, significantly reducing TB load in murine lungs, ameliorating pulmonary pathology, and enhancing immune responses. Transcriptome analysis of draining lymph nodes after vaccination with either BCG ΔureC::hly or BCG ΔureC::hly ΔnuoG demonstrated earlier and stronger induction of immune responses than that with BCG SSI and suggested upregulation of inflammasome activation and interferon-induced GTPases. In summary, BCG ΔureC::hly ΔnuoG is a promising next-generation TB vaccine candidate with excellent efficacy and safety. IMPORTANCE Autophagy and apoptosis are fundamental processes allowing cells to degrade their components or kill themselves, respectively. The immune system has adopted these mechanisms to eliminate intracellular pathogens. Residing in host cells, the causative agent of tuberculosis, Mycobacterium tuberculosis, has evolved strategies to set cellular programs of autophagy and apoptosis “on hold.” The mycobacterial gene nuoG was found to prevent host cell apoptosis. We have deleted nuoG in the live vaccine candidate BCG ΔureC::hly, which is in phase II clinical development, to leave cellular apoptosis “on go” upon immunization. In preclinical models, this strategy boosted immunity and improved protection from M. tuberculosis infection. Unexpectedly, we obtained compelling evidence that mycobacterial nuoG facilitates inhibition of autophagic pathways, suggesting a new role for this gene in the host-pathogen interplay in tuberculosis. |
| format |
article |
| author |
Martin Gengenbacher Natalie Nieuwenhuizen Alexis Vogelzang Haipeng Liu Peggy Kaiser Stefanie Schuerer Doris Lazar Ina Wagner Hans-Joachim Mollenkopf Stefan H. E. Kaufmann |
| author_facet |
Martin Gengenbacher Natalie Nieuwenhuizen Alexis Vogelzang Haipeng Liu Peggy Kaiser Stefanie Schuerer Doris Lazar Ina Wagner Hans-Joachim Mollenkopf Stefan H. E. Kaufmann |
| author_sort |
Martin Gengenbacher |
| title |
Deletion of <italic toggle="yes">nuoG</italic> from the Vaccine Candidate <named-content content-type="genus-species">Mycobacterium bovis</named-content> BCG Δ<italic toggle="yes">ureC</italic>::<italic toggle="yes">hly</italic> Improves Protection against Tuberculosis |
| title_short |
Deletion of <italic toggle="yes">nuoG</italic> from the Vaccine Candidate <named-content content-type="genus-species">Mycobacterium bovis</named-content> BCG Δ<italic toggle="yes">ureC</italic>::<italic toggle="yes">hly</italic> Improves Protection against Tuberculosis |
| title_full |
Deletion of <italic toggle="yes">nuoG</italic> from the Vaccine Candidate <named-content content-type="genus-species">Mycobacterium bovis</named-content> BCG Δ<italic toggle="yes">ureC</italic>::<italic toggle="yes">hly</italic> Improves Protection against Tuberculosis |
| title_fullStr |
Deletion of <italic toggle="yes">nuoG</italic> from the Vaccine Candidate <named-content content-type="genus-species">Mycobacterium bovis</named-content> BCG Δ<italic toggle="yes">ureC</italic>::<italic toggle="yes">hly</italic> Improves Protection against Tuberculosis |
| title_full_unstemmed |
Deletion of <italic toggle="yes">nuoG</italic> from the Vaccine Candidate <named-content content-type="genus-species">Mycobacterium bovis</named-content> BCG Δ<italic toggle="yes">ureC</italic>::<italic toggle="yes">hly</italic> Improves Protection against Tuberculosis |
| title_sort |
deletion of <italic toggle="yes">nuog</italic> from the vaccine candidate <named-content content-type="genus-species">mycobacterium bovis</named-content> bcg δ<italic toggle="yes">urec</italic>::<italic toggle="yes">hly</italic> improves protection against tuberculosis |
| publisher |
American Society for Microbiology |
| publishDate |
2016 |
| url |
https://doaj.org/article/a3795285567a431ba72958df4832df9e |
| work_keys_str_mv |
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