Metabolic deficiencies underlie reduced plasmacytoid dendritic cell IFN-I production following viral infection
Abstract Type I Interferons (IFN-I) are central to host protection against viral infections, with plasmacytoid dendritic cells (pDC) being the most significant source, yet pDCs lose their IFN-I production capacity following an initial burst of IFN-I, resulting in susceptibility to secondary infectio...
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| Format: | Article |
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Nature Portfolio
2025-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56603-5 |
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| author | Trever T. Greene Yeara Jo Carolina Chiale Monica Macal Ziyan Fang Fawziyah S. Khatri Alicia L. Codrington Katelynn R. Kazane Elizabeth Akbulut Shobha Swaminathan Yu Fujita Patricia Fitzgerald-Bocarsly Thekla Cordes Christian Metallo David A. Scott Elina I. Zúñiga |
| author_facet | Trever T. Greene Yeara Jo Carolina Chiale Monica Macal Ziyan Fang Fawziyah S. Khatri Alicia L. Codrington Katelynn R. Kazane Elizabeth Akbulut Shobha Swaminathan Yu Fujita Patricia Fitzgerald-Bocarsly Thekla Cordes Christian Metallo David A. Scott Elina I. Zúñiga |
| author_sort | Trever T. Greene |
| collection | DOAJ |
| description | Abstract Type I Interferons (IFN-I) are central to host protection against viral infections, with plasmacytoid dendritic cells (pDC) being the most significant source, yet pDCs lose their IFN-I production capacity following an initial burst of IFN-I, resulting in susceptibility to secondary infections. The underlying mechanisms of these dynamics are not well understood. Here we find that viral infection reduces the capacity of pDCs to engage both oxidative and glycolytic metabolism. Mechanistically, we identify lactate dehydrogenase B (LDHB) as a positive regulator of pDC IFN-I production in mice and humans; meanwhile, LDHB deficiency is associated with suppressed IFN-I production, pDC metabolic capacity, and viral control following infection. In addition, preservation of LDHB expression is sufficient to partially retain the function of otherwise exhausted pDCs, both in vitro and in vivo. Furthermore, restoring LDHB in vivo in pDCs from infected mice increases IFNAR-dependent, infection-associated pathology. Our work thus identifies a mechanism for balancing immunity and pathology during viral infections, while also providing insight into the highly preserved infection-driven pDC inhibition. |
| format | Article |
| id | doaj-art-5b08216b5e0049c599210f9c2d60e07b |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-5b08216b5e0049c599210f9c2d60e07b2025-02-09T12:46:24ZengNature PortfolioNature Communications2041-17232025-02-0116111910.1038/s41467-025-56603-5Metabolic deficiencies underlie reduced plasmacytoid dendritic cell IFN-I production following viral infectionTrever T. Greene0Yeara Jo1Carolina Chiale2Monica Macal3Ziyan Fang4Fawziyah S. Khatri5Alicia L. Codrington6Katelynn R. Kazane7Elizabeth Akbulut8Shobha Swaminathan9Yu Fujita10Patricia Fitzgerald-Bocarsly11Thekla Cordes12Christian Metallo13David A. Scott14Elina I. Zúñiga15Department of Biological Sciences, University of California, San DiegoDepartment of Biological Sciences, University of California, San DiegoDepartment of Biological Sciences, University of California, San DiegoDepartment of Biological Sciences, University of California, San DiegoDepartment of Biological Sciences, University of California, San DiegoDepartment of Biological Sciences, University of California, San DiegoDepartment of Pathology, Immunology and Laboratory Medicine, Rutgers New Jersey Medical SchoolDepartment of Biological Sciences, University of California, San DiegoDepartment of Pathology, Immunology and Laboratory Medicine, Rutgers New Jersey Medical SchoolDepartment of Medicine, Division of Infectious Disease, The State University of New Jersey, Rutgers, New Jersey Medical SchoolDivision of Next-Generation Drug Development, Research Center for Medical Sciences, The Jikei University School of MedicineDepartment of Pathology, Immunology and Laboratory Medicine, Rutgers New Jersey Medical SchoolDepartment of Bioinformatics and Biochemistry, Braunschweig Integrated Centre of Systems Biology (BRICS), Technische Universität BraunschweigMolecular and Cell Biology Laboratory, Salk Institute for Biological SciencesCancer Center, Sanford Burnham Prebys Medical Discovery InstituteDepartment of Biological Sciences, University of California, San DiegoAbstract Type I Interferons (IFN-I) are central to host protection against viral infections, with plasmacytoid dendritic cells (pDC) being the most significant source, yet pDCs lose their IFN-I production capacity following an initial burst of IFN-I, resulting in susceptibility to secondary infections. The underlying mechanisms of these dynamics are not well understood. Here we find that viral infection reduces the capacity of pDCs to engage both oxidative and glycolytic metabolism. Mechanistically, we identify lactate dehydrogenase B (LDHB) as a positive regulator of pDC IFN-I production in mice and humans; meanwhile, LDHB deficiency is associated with suppressed IFN-I production, pDC metabolic capacity, and viral control following infection. In addition, preservation of LDHB expression is sufficient to partially retain the function of otherwise exhausted pDCs, both in vitro and in vivo. Furthermore, restoring LDHB in vivo in pDCs from infected mice increases IFNAR-dependent, infection-associated pathology. Our work thus identifies a mechanism for balancing immunity and pathology during viral infections, while also providing insight into the highly preserved infection-driven pDC inhibition.https://doi.org/10.1038/s41467-025-56603-5 |
| spellingShingle | Trever T. Greene Yeara Jo Carolina Chiale Monica Macal Ziyan Fang Fawziyah S. Khatri Alicia L. Codrington Katelynn R. Kazane Elizabeth Akbulut Shobha Swaminathan Yu Fujita Patricia Fitzgerald-Bocarsly Thekla Cordes Christian Metallo David A. Scott Elina I. Zúñiga Metabolic deficiencies underlie reduced plasmacytoid dendritic cell IFN-I production following viral infection Nature Communications |
| title | Metabolic deficiencies underlie reduced plasmacytoid dendritic cell IFN-I production following viral infection |
| title_full | Metabolic deficiencies underlie reduced plasmacytoid dendritic cell IFN-I production following viral infection |
| title_fullStr | Metabolic deficiencies underlie reduced plasmacytoid dendritic cell IFN-I production following viral infection |
| title_full_unstemmed | Metabolic deficiencies underlie reduced plasmacytoid dendritic cell IFN-I production following viral infection |
| title_short | Metabolic deficiencies underlie reduced plasmacytoid dendritic cell IFN-I production following viral infection |
| title_sort | metabolic deficiencies underlie reduced plasmacytoid dendritic cell ifn i production following viral infection |
| url | https://doi.org/10.1038/s41467-025-56603-5 |
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