Mucosal exposure to non-tuberculous mycobacteria elicits B cell-mediated immunity against pulmonary tuberculosis

Dutt, Taru; Karger, Burton; Fox, Amy; Youssef, Nathan; Dadhwal, Rhythm; Ali, Malik Zohaib; Patterson, Johnathan; Creissen, Elizabeth; Rampacci, Elisa; Cooper, Sarah K.; Podell, Brendan K.; González-Juarrero, Mercedes; Obregón-Henao, Andrés; Henao-Tamayo, Marcela

doi:10.1016/j.celrep.2022.111783

Cited by 11 publications

(16 citation statements)

References 105 publications

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“…In studies of both humans and mice, there are mixed reports on the effect of NTM exposure on BCG vaccination efficacy and the protection against TB. 6 , 70 , 71 , 72 While the results of these studies are difficult to interpret due to differences in the species, dose, route, and duration of NTM exposure, a recent study showed that continuous exposure of BCG vaccinated and unvaccinated mice to NTM via drinking water induced strong airway and systemic IgG and IgA responses to Mtb lysates and enhanced survival of mice after Mtb infection. 73 Collectively with our results, these data support that NTM exposure can have protective effects against TB.…”

Section: Discussionmentioning

confidence: 99%

“…It protects against disseminated TB in children but has limited protection against pulmonary TB during childhood or TB later in life. 2 , 3 Its effect on reduction of initial infection with Mycobacterium tuberculosis ( Mtb ) is controversial, 4 , 5 , 6 with recent data suggesting that i. d. BCG revaccination in adolescents can reduce the rate of sustained new IGRA conversion. 7 , 8 Nevertheless, around a quarter of the world's population is estimated to be infected with Mtb .…”

Section: Introductionmentioning

confidence: 99%

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Mucosal and systemic antigen-specific antibody responses correlate with protection against active tuberculosis in nonhuman primates

Ishida,

Corrigan,

Chen

et al. 2024

eBioMedicine

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mucosal and systemic antigen-specific antibody responses correlate with protection against active tuberculosis in nonhuman primates

Ishida,

Corrigan,

Chen

et al. 2024

eBioMedicine

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“…Sections from formalin fixed and paraffin embedded (FFPE) tissues were cut at 5 µm, stained with hematoxylin and eosin (H&E) and scanned at 40X magnification using multispectral automated PhenoImager (Akoya Biosciences) for histopathological evaluation. The extent of lung lesion burden was quantified in blinded digital images using an open-source QuPath software for image analysis as described previously (56).…”

Section: Histopathology and Lesion Scoringmentioning

confidence: 99%

“…Single cell suspension of bone marrow, blood, and lungs from C3HeB/FeJ mice was prepared as described previously (56). Cells counting, viability staining and cell staining (Table S1) was performed accordingly (56). Samples were acquired using Cytek Aurora TM 4-Laser spectral flow cytometer where 100,000 events were recorded.…”

Section: Immune Cell Populations Analysismentioning

confidence: 99%

A Modified BPaL Regimen for Tuberculosis Treatment replaces Linezolid with Inhaled Spectinamides

Ali,

Dutt,

MacNeill

et al. 2023

Preprint

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The Nix-TB clinical trial evaluated a new 6-month regimen containing three-oral-drugs; bedaquiline (B), pretomanid (Pa) and linezolid (L) (BPaL regimen) for treatment of tuberculosis (TB). This regimen achieved remarkable results as almost 90% of the multidrug resistant (MDR) or extensively drug resistant (XDR) TB participants were cured but many patients also developed severe adverse effects (AEs). The AEs were associated with the long-term administration of the protein synthesis inhibitor linezolid. Spectinamide 1599 (S) is also a protein synthesis inhibitor ofMycobacterium tuberculosiswith an excellent safety profile but which lacks oral bioavailability. Here we hypothesize that inhaled spectinamide 1599, combined with BPa ––BPaS regimen––has similar efficacy to that of BPaL regimen while simultaneously avoiding the L-associated AEs. The BPaL and BPaS regimens were compared in the Balb/c and C3HeB/FeJ murine chronic TB efficacy models. After 4-weeks of treatment, both regimens promoted equivalent bactericidal effect in both TB murine models. However, treatment with BPaL resulted in significant weight loss and the complete blood count suggested development of anemia. These effects were not similarly observed in mice treated with BPaS. BPaL treatment also decreased myeloid to erythroid ratio and increased concentration of proinflammatory cytokines in bone marrow compared to mice receiving BPaS regimen. During therapy both regimens improved the lung lesion burden, reduced neutrophil and cytotoxic T cells counts while increased the number of B and helper and regulatory T cells. These combined data suggest that inhaled spectinamide 1599 combined with BPa is an effective TB regimen that avoids L-associated AEs.IMPORTANCETuberculosis (TB) is an airborne infectious disease that spreads via aerosols containingMycobacterium tuberculosis(Mtb), the causative agent of TB. TB can be cured by administration of 3-4 drugs for 6-9 months but there are limited treatment options for patients infected with multidrug (MDR) and extensively resistant (XDR) strains of Mtb. BPaL is a new all-oral combination of drugs consisting of Bedaquiline (B), Pretomanid (Pa) and Linezolid (L). This regimen was able to cure ∼90% of MDR and XDR TB patients in clinical trials but many patients developed severe adverse effects (AEs) associated to the long-term administration of linezolid. We evaluated a new regimen in which Linezolid in the BPaL regimen was replaced with inhaled spectinamide 1599. In the current study, we demonstrate that 4-weeks of treatment with inhaled spectinamide 1599 in combination with Bedaquiline and Pretomanid has equivalent efficacy to the BPaL drug combination and avoids the L-associated-AEs.

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“…Exposure to environmental non-tuberculous mycobacteria (NTM) has been proposed as a cause for the variable efficacy of BCG, especially in tropical regions in which BCG efficacy is inversely proportional to the prevalence of NTM [9][10][11][12] . A recent study showed that mucosal exposure to NTM elicits protective B cell-mediated immunity and enhances protection against M. tuberculosis challenge of mice 13 . If environmental exposure to NTM provides protection against M. tuberculosis in some populations, any benefit of BCG vaccination might be nullified in this setting.…”

Section: Introductionmentioning

confidence: 99%

Key advances in vaccine development for tuberculosis—success and challenges

Lai,

Ogunsola,

Rakib

et al. 2023

npj Vaccines

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Breakthrough findings in the clinical and preclinical development of tuberculosis (TB) vaccines have galvanized the field and suggest, for the first time since the development of bacille Calmette-Guérin (BCG), that a novel and protective TB vaccine is on the horizon. Here we highlight the TB vaccines that are in the development pipeline and review the basis for optimism in both the clinical and preclinical space. We describe immune signatures that could act as immunological correlates of protection (CoP) to facilitate the development and comparison of vaccines. Finally, we discuss new animal models that are expected to more faithfully model the pathology and complex immune responses observed in human populations.

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Mucosal exposure to non-tuberculous mycobacteria elicits B cell-mediated immunity against pulmonary tuberculosis

Cited by 11 publications

References 105 publications

Mucosal and systemic antigen-specific antibody responses correlate with protection against active tuberculosis in nonhuman primates

Mucosal and systemic antigen-specific antibody responses correlate with protection against active tuberculosis in nonhuman primates

A Modified BPaL Regimen for Tuberculosis Treatment replaces Linezolid with Inhaled Spectinamides

Key advances in vaccine development for tuberculosis—success and challenges

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