Interferon-gamma rescues dendritic cell calcineurin-dependent responses to Aspergillus fumigatus via Stat3 to Stat1 switching
Summary: Invasive pulmonary aspergillosis is a lethal opportunistic fungal infection in transplant recipients receiving calcineurin inhibitors. We previously identified a role for the calcineurin pathway in innate immune responses to A. fumigatus and have used exogenous interferon-gamma successfully...
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Elsevier
2025-02-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004224027627 |
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| author | Amit Adlakha Thomas J. Williams Xinxin Shou Anna K. Reed Boris Lenhard Darius Armstrong-James |
| author_facet | Amit Adlakha Thomas J. Williams Xinxin Shou Anna K. Reed Boris Lenhard Darius Armstrong-James |
| author_sort | Amit Adlakha |
| collection | DOAJ |
| description | Summary: Invasive pulmonary aspergillosis is a lethal opportunistic fungal infection in transplant recipients receiving calcineurin inhibitors. We previously identified a role for the calcineurin pathway in innate immune responses to A. fumigatus and have used exogenous interferon-gamma successfully to treat aspergillosis in this setting. Here we show that calcineurin inhibitors block dendritic cell maturation in response to A. fumigatus, impairing the Th1 polarization of CD4 cells. Interferon gamma, an immunotherapeutic option for invasive aspergillosis, restored maturation and promoted Th1 polarization via a dendritic cell dependent effect that was co-dependent on T cell interaction. We find that interferon gamma activates alternative transcriptional pathways to calcineurin-NFAT for the augmentation of pathogen handling. Histone modification ChIP-Seq analysis revealed dominant control by an interferon gamma induced regulatory switch from STAT3 to STAT1 transcription factor binding underpinning these observations. These findings provide key insight into the mechanisms of immunotherapy in organ transplant recipients with invasive fungal diseases. |
| format | Article |
| id | doaj-art-5816beef59fb49dfa785c0b1f0e56fcc |
| institution | Kabale University |
| issn | 2589-0042 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj-art-5816beef59fb49dfa785c0b1f0e56fcc2025-01-18T05:05:03ZengElsevieriScience2589-00422025-02-01282111535Interferon-gamma rescues dendritic cell calcineurin-dependent responses to Aspergillus fumigatus via Stat3 to Stat1 switchingAmit Adlakha0Thomas J. Williams1Xinxin Shou2Anna K. Reed3Boris Lenhard4Darius Armstrong-James5Department of Infectious Disease, Faculty of Medicine, Imperial College, London SW7 2AZ, UK; MRC London Institute of Medical Sciences, Imperial College, London W12 0NN, UK; Department of Cardiothoracic Transplantation and Mechanical Support, Harefield Hospital, Royal Brompton & Harefield Hospitals, Part of Guy’s and St. Thomas' NHS Foundation Trust & Imperial College, London UB9 6JH, UKDepartment of Infectious Disease, Faculty of Medicine, Imperial College, London SW7 2AZ, UK; Department of Cardiothoracic Transplantation and Mechanical Support, Harefield Hospital, Royal Brompton & Harefield Hospitals, Part of Guy’s and St. Thomas' NHS Foundation Trust & Imperial College, London UB9 6JH, UKDepartment of Infectious Disease, Faculty of Medicine, Imperial College, London SW7 2AZ, UKDepartment of Cardiothoracic Transplantation and Mechanical Support, Harefield Hospital, Royal Brompton & Harefield Hospitals, Part of Guy’s and St. Thomas' NHS Foundation Trust & Imperial College, London UB9 6JH, UKMRC London Institute of Medical Sciences, Imperial College, London W12 0NN, UKDepartment of Infectious Disease, Faculty of Medicine, Imperial College, London SW7 2AZ, UK; Department of Cardiothoracic Transplantation and Mechanical Support, Harefield Hospital, Royal Brompton & Harefield Hospitals, Part of Guy’s and St. Thomas' NHS Foundation Trust & Imperial College, London UB9 6JH, UK; Corresponding authorSummary: Invasive pulmonary aspergillosis is a lethal opportunistic fungal infection in transplant recipients receiving calcineurin inhibitors. We previously identified a role for the calcineurin pathway in innate immune responses to A. fumigatus and have used exogenous interferon-gamma successfully to treat aspergillosis in this setting. Here we show that calcineurin inhibitors block dendritic cell maturation in response to A. fumigatus, impairing the Th1 polarization of CD4 cells. Interferon gamma, an immunotherapeutic option for invasive aspergillosis, restored maturation and promoted Th1 polarization via a dendritic cell dependent effect that was co-dependent on T cell interaction. We find that interferon gamma activates alternative transcriptional pathways to calcineurin-NFAT for the augmentation of pathogen handling. Histone modification ChIP-Seq analysis revealed dominant control by an interferon gamma induced regulatory switch from STAT3 to STAT1 transcription factor binding underpinning these observations. These findings provide key insight into the mechanisms of immunotherapy in organ transplant recipients with invasive fungal diseases.http://www.sciencedirect.com/science/article/pii/S2589004224027627PathophysiologyMicrobiologyTranscriptomics |
| spellingShingle | Amit Adlakha Thomas J. Williams Xinxin Shou Anna K. Reed Boris Lenhard Darius Armstrong-James Interferon-gamma rescues dendritic cell calcineurin-dependent responses to Aspergillus fumigatus via Stat3 to Stat1 switching iScience Pathophysiology Microbiology Transcriptomics |
| title | Interferon-gamma rescues dendritic cell calcineurin-dependent responses to Aspergillus fumigatus via Stat3 to Stat1 switching |
| title_full | Interferon-gamma rescues dendritic cell calcineurin-dependent responses to Aspergillus fumigatus via Stat3 to Stat1 switching |
| title_fullStr | Interferon-gamma rescues dendritic cell calcineurin-dependent responses to Aspergillus fumigatus via Stat3 to Stat1 switching |
| title_full_unstemmed | Interferon-gamma rescues dendritic cell calcineurin-dependent responses to Aspergillus fumigatus via Stat3 to Stat1 switching |
| title_short | Interferon-gamma rescues dendritic cell calcineurin-dependent responses to Aspergillus fumigatus via Stat3 to Stat1 switching |
| title_sort | interferon gamma rescues dendritic cell calcineurin dependent responses to aspergillus fumigatus via stat3 to stat1 switching |
| topic | Pathophysiology Microbiology Transcriptomics |
| url | http://www.sciencedirect.com/science/article/pii/S2589004224027627 |
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