Integrated Organ Immunity: Antigen-specific CD4-T cell-derived IFN-γ induced by BCG imprints prolonged lung innate resistance against respiratory viruses
ABSTRACT Bacille Calmette-Guérin (BCG) vaccination can confer non-specific protection against heterologous pathogens. However, the underlying mechanisms remain mysterious. Here, we show that mice immunized intravenously with BCG exhibited reduced weight loss and/or improved viral clearance when challenged with SARS-CoV-2 and influenza. Protection was first evident between 14 - 21 days post vaccination, and lasted for at least 42 days. Remarkably, BCG induced a biphasic innate response in the lung, initially at day 1 and a subsequent prolonged phase starting at ∼15 days post vaccination, and robust antigen-specific Th1 responses. MyD88-dependent TLR signaling was essential for the induction of the innate and Th1 responses, and protection against SARS-CoV-2. Depletion of CD4+T cells or IFN-γ activity prior to infection obliterated innate activation and protection. Single cell and spatial transcriptomics revealed CD4-dependent expression of interferon-stimulated genes (ISGs) in myeloid, type II alveolar and lung epithelial cells. Thus, BCG elicits “integrated organ immunity” where CD4+ T cells act on local myeloid and epithelial cells to imprint prolonged antiviral innate resistance..
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Preprint| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
bioRxiv.org - (2023) vom: 04. Aug. Zur Gesamtaufnahme - year:2023 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Lee, Audrey [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.1101/2023.07.31.551354 |
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| PPN (Katalog-ID): |
XBI040402851 |
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| 520 | |a ABSTRACT Bacille Calmette-Guérin (BCG) vaccination can confer non-specific protection against heterologous pathogens. However, the underlying mechanisms remain mysterious. Here, we show that mice immunized intravenously with BCG exhibited reduced weight loss and/or improved viral clearance when challenged with SARS-CoV-2 and influenza. Protection was first evident between 14 - 21 days post vaccination, and lasted for at least 42 days. Remarkably, BCG induced a biphasic innate response in the lung, initially at day 1 and a subsequent prolonged phase starting at ∼15 days post vaccination, and robust antigen-specific Th1 responses. MyD88-dependent TLR signaling was essential for the induction of the innate and Th1 responses, and protection against SARS-CoV-2. Depletion of CD4+T cells or IFN-γ activity prior to infection obliterated innate activation and protection. Single cell and spatial transcriptomics revealed CD4-dependent expression of interferon-stimulated genes (ISGs) in myeloid, type II alveolar and lung epithelial cells. Thus, BCG elicits “integrated organ immunity” where CD4+ T cells act on local myeloid and epithelial cells to imprint prolonged antiviral innate resistance. | ||
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| 700 | 1 | |a Fang, Zhuoqing |4 aut | |
| 700 | 1 | |a Tan, Tze Kai |4 aut | |
| 700 | 1 | |a Li, Chunfeng |4 aut | |
| 700 | 1 | |a Hui, Harold |4 aut | |
| 700 | 1 | |a Scoville, David |4 aut | |
| 700 | 1 | |a Ruggiero, Alistaire D. |4 aut | |
| 700 | 1 | |a Liang, Yan |4 aut | |
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| 700 | 1 | |a Pulendran, Bali |4 aut | |
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