Protective intravenous BCG vaccination induces enhanced immune signaling in the airways
Intradermal (ID) Bacillus Calmette-Guérin (BCG) is the most widely administered vaccine in the world. However, ID-BCG fails to achieve the level of protection needed in adults to alter the course of the tuberculosis epidemic. Recent studies in non-human primates have demonstrated high levels of protection against Mycobacterium tuberculosis ( Mtb ) following intravenous (IV) administration of BCG. However, the protective immune features that emerge following IV BCG vaccination remain incompletely defined. Here we used single-cell RNA-sequencing (scRNAseq) to transcriptionally profile 157,114 unstimulated and purified protein derivative (PPD)-stimulated bronchoalveolar lavage (BAL) cells from 29 rhesus macaques immunized with BCG across routes of administration and doses to uncover cell composition-, gene expression-, and biological network-level signatures associated with IV BCG-mediated protection. Our analyses revealed that high-dose IV BCG drove an influx of polyfunctional T cells and macrophages into the airways. These macrophages exhibited a basal activation phenotype even in the absence of PPD-stimulation, defined in part by IFN and TNF-α signaling up to 6 months following BCG immunization. Furthermore, intercellular immune signaling pathways between key myeloid and T cell subsets were enhanced following PPD-stimulation in high-dose IV BCG-vaccinated macaques. High-dose IV BCG also engendered quantitatively and qualitatively stronger transcriptional responses to PPD-stimulation, with a robust Th1-Th17 transcriptional phenotype in T cells, and augmented transcriptional signatures of reactive oxygen species production, hypoxia, and IFN-γ response within alveolar macrophages. Collectively, this work supports that IV BCG immunization creates a unique cellular ecosystem in the airways, which primes and enables local myeloid cells to effectively clear Mtb upon challenge.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2023 |
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| Enthalten in: |
bioRxiv : the preprint server for biology - (2023) vom: 18. Juli |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Peters, Joshua M [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Revised 28.07.2023 published: Electronic Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1101/2023.07.16.549208 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM360028098 |
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| 520 | |a Intradermal (ID) Bacillus Calmette-Guérin (BCG) is the most widely administered vaccine in the world. However, ID-BCG fails to achieve the level of protection needed in adults to alter the course of the tuberculosis epidemic. Recent studies in non-human primates have demonstrated high levels of protection against Mycobacterium tuberculosis ( Mtb ) following intravenous (IV) administration of BCG. However, the protective immune features that emerge following IV BCG vaccination remain incompletely defined. Here we used single-cell RNA-sequencing (scRNAseq) to transcriptionally profile 157,114 unstimulated and purified protein derivative (PPD)-stimulated bronchoalveolar lavage (BAL) cells from 29 rhesus macaques immunized with BCG across routes of administration and doses to uncover cell composition-, gene expression-, and biological network-level signatures associated with IV BCG-mediated protection. Our analyses revealed that high-dose IV BCG drove an influx of polyfunctional T cells and macrophages into the airways. These macrophages exhibited a basal activation phenotype even in the absence of PPD-stimulation, defined in part by IFN and TNF-α signaling up to 6 months following BCG immunization. Furthermore, intercellular immune signaling pathways between key myeloid and T cell subsets were enhanced following PPD-stimulation in high-dose IV BCG-vaccinated macaques. High-dose IV BCG also engendered quantitatively and qualitatively stronger transcriptional responses to PPD-stimulation, with a robust Th1-Th17 transcriptional phenotype in T cells, and augmented transcriptional signatures of reactive oxygen species production, hypoxia, and IFN-γ response within alveolar macrophages. Collectively, this work supports that IV BCG immunization creates a unique cellular ecosystem in the airways, which primes and enables local myeloid cells to effectively clear Mtb upon challenge | ||
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| 700 | 1 | |a Irvine, Edward B |e verfasserin |4 aut | |
| 700 | 1 | |a Rosenberg, Jacob M |e verfasserin |4 aut | |
| 700 | 1 | |a Wadsworth, Marc H |e verfasserin |4 aut | |
| 700 | 1 | |a Hughes, Travis K |e verfasserin |4 aut | |
| 700 | 1 | |a Sutton, Matthew |e verfasserin |4 aut | |
| 700 | 1 | |a Nyquist, Sarah K |e verfasserin |4 aut | |
| 700 | 1 | |a Bromley, Joshua D |e verfasserin |4 aut | |
| 700 | 1 | |a Mondal, Rajib |e verfasserin |4 aut | |
| 700 | 1 | |a Roederer, Mario |e verfasserin |4 aut | |
| 700 | 1 | |a Seder, Robert A |e verfasserin |4 aut | |
| 700 | 1 | |a Darrah, Patricia A |e verfasserin |4 aut | |
| 700 | 1 | |a Alter, Galit |e verfasserin |4 aut | |
| 700 | 1 | |a Flynn, JoAnne L |e verfasserin |4 aut | |
| 700 | 1 | |a Shalek, Alex K |e verfasserin |4 aut | |
| 700 | 1 | |a Fortune, Sarah M |e verfasserin |4 aut | |
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