Immunotherapy targeting drug-tolerant Mycobacterium tuberculosis persisters accelerates tuberculosis cure in preclinical models
Styliani Karanika, Tianyin Wang, Addis Yilma, Jennie Ruelas Castillo, James T. Gordy, Hannah Bailey, Darla Quijada, Kaitlyn Fessler, Rokeya Tasneen, Elisa M. Rouse Salcido, Farah Shamma, Harley T. Harris, Fengyixin Chen, Rowan E. Bates, Heemee Ton, Jacob Meza, Yangchen Li, Alannah D. Taylor, Jean J. Zheng, Jiaqi Zhang, Theodoros Karantanos, Amanda R. Maxwell, Eric Nuermberger, J David Peske, Richard B. Markham, Petros C. Karakousis
Styliani Karanika, Tianyin Wang, Addis Yilma, Jennie Ruelas Castillo, James T. Gordy, Hannah Bailey, Darla Quijada, Kaitlyn Fessler, Rokeya Tasneen, Elisa M. Rouse Salcido, Farah Shamma, Harley T. Harris, Fengyixin Chen, Rowan E. Bates, Heemee Ton, Jacob Meza, Yangchen Li, Alannah D. Taylor, Jean J. Zheng, Jiaqi Zhang, Theodoros Karantanos, Amanda R. Maxwell, Eric Nuermberger, J David Peske, Richard B. Markham, Petros C. Karakousis
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Research Article Immunology Infectious disease

Immunotherapy targeting drug-tolerant Mycobacterium tuberculosis persisters accelerates tuberculosis cure in preclinical models

Abstract

Mycobacterium tuberculosis remains a global health crisis, ranking among the deadliest infectious diseases worldwide. In response to the WHO’s call for therapeutic vaccines to complement antibiotic regimens and reduce tuberculosis (TB) treatment duration, we developed an intranasal DNA vaccine fusing the M. tuberculosis stringent response gene relMtb with the gene encoding the DC-targeting chemokine Mip3a (also known as CCL20). Administered alongside the first-line regimen, this vaccine accelerated a stable cure in immunocompetent murine TB models, reducing lung inflammation and eliciting robust and sustained RelMtb-stimulated T cell responses systemically and locally. The Mip3a/relMtb vaccine enhanced DC recruitment, activation, and spatial coordination with T cells, suggesting improved innate-adaptive immune synergy. Notably, it augmented the efficacy of a novel drug-resistant TB regimen as well. Critically, the vaccine induced analogous antigen-stimulated T cell immunity in nonhuman primates, the gold standard for preclinical TB vaccine evaluation, with responses detected in blood and bronchoalveolar lavage mirroring those observed in the murine models. These findings underscore the potential of this strategy to advance therapeutic TB vaccine development targeting M. tuberculosis persisters while providing a framework to define correlates of vaccine-mediated protection.

Authors

Styliani Karanika, Tianyin Wang, Addis Yilma, Jennie Ruelas Castillo, James T. Gordy, Hannah Bailey, Darla Quijada, Kaitlyn Fessler, Rokeya Tasneen, Elisa M. Rouse Salcido, Farah Shamma, Harley T. Harris, Fengyixin Chen, Rowan E. Bates, Heemee Ton, Jacob Meza, Yangchen Li, Alannah D. Taylor, Jean J. Zheng, Jiaqi Zhang, Theodoros Karantanos, Amanda R. Maxwell, Eric Nuermberger, J David Peske, Richard B. Markham, Petros C. Karakousis

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Figure 5

Therapeutic IN Mip3a/relMtb fusion immunization induces local DC infiltration, enhancing colocalization with T cells in mouse lungs.

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Therapeutic IN Mip3a/relMtb fusion immunization induces local DC infiltr...
(A and B) Representative lung sections (whole slides, rich DC–T cell fields of view and DC–T cell spatial plots) from RHZE alone (A) versus IN Mip3a/relMtb plus RHZE after 12 weeks of treatment (B) stained with antibodies for DAPI+ only (dark blue, cell nuclei, top) or CD45+ (white, hematopoietic cells, bottom), CD45+CD3+ (red, T cells, bottom), and CD45+CD3-CD11c+F4/80– (yellow, DCs, bottom). Light brown arrows in low-magnification images (scale bars: 1 mm) indicate the specific areas shown in the corresponding high-magnification images (scale bars: 50 μm). Magenta arrows indicate DC–T cell colocalization. (C and D) Quantification of total DCls per DAPI+ cells (percentage) and colocalization of DCs and T cells defined as the number of DCs within 10 μm of T cells (RHZE alone [n = 6] vs. IN Mip3a/relMtb plus RHZE [n = 4]). Assessment was performed on sections encompassing the entire left lung. *P < 0.05, by Mann-Whitney U test.