Integrated Organ Immunity: Antigen-specific CD4-T cell-derived IFN-γ induced by BCG imprints prolonged lung innate resistance against respiratory viruses

Lee, A.; Floyd, K.; Wu, S.-Y.; Fang, Z.; Tan, T. K.; Li, C.; Hui, H.; Scoville, D.; Ruggiero, A.; Liang, Y.; Pavenko, A.; Lujan, V.; Nolan, G. P.; Arunachalam, P.; Suthar, M.; Pulendran, B.

doi:10.1101/2023.07.31.551354

bioRxiv · 10.1101/2023.07.31.551354

Integrated Organ Immunity: Antigen-specific CD4-T cell-derived IFN-γ induced by BCG imprints prolonged lung innate resistance against respiratory viruses

Lee, A.·Floyd, K.·Wu, S.-Y.·Fang, Z.·Tan, T. K.·Li, C.·Hui, H.·Scoville, D.·Ruggiero, A.·Liang, Y.·Pavenko, A.·Lujan, V.·Nolan, G. P.·Arunachalam, P.·Suthar, M.·Pulendran, B.

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Abstract

Bacille Calmette-Guerin (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-{gamma} 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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Lee, A., Floyd, K., Wu, S.-Y., Fang, Z., Tan, T. K., Li, C., Hui, H., Scoville, D., Ruggiero, A., Liang, Y., Pavenko, A., Lujan, V., Nolan, G. P., Arunachalam, P., Suthar, M., Pulendran, B.. 2023-08-02. Integrated Organ Immunity: Antigen-specific CD4-T cell-derived IFN-γ induced by BCG imprints prolonged lung innate resistance against respiratory viruses. https://doi.org/10.1101/2023.07.31.551354

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