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Researchers Uncover Metabolism Link to Proteins Important in Infections, Cancer and Autoimmunity
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Not long after a threatening organism enters our bodies, our immune system springs into action and starts producing proteins known as type one interferons (IFN-I), which fight viruses and cancer, while also playing pathogenic roles in autoimmune disorders. While all cells can produce low amounts of these anti-viral and anti-tumor proteins, one particular cell type, termed plasmacytoid dendritic cells (pDCs), stands out as a specialized IFN-I producer. These specialists are capable of generating up to 1,000 times more and a broader range of IFN-I subtypes within hours of encountering a pathogen, compared with any other cell in our body. This powerful IFN-I burst is, however, short-lived. At later stages of infection and within tumors, pDCs exhibit a sharp decline in IFN-I production.
Immunologists have long focused on understanding the early, robust IFN-I response of pDCs, yet a critical gap remains: Why do pDCs stop producing IFN-I after this initial wave? What mechanisms drive their suppression at later stages of infection? Unraveling this process is key to harnessing pDC function for therapeutic interventions in infections, cancer and potentially suppressing pathogenic IFN-I in autoimmune disorders.
Professor Elina Zúñiga of the UC San Diego School of Biological Sciences and her colleagues have uncovered critical mechanisms underlying pDC suppression after infection. For the first time, the researchers identified that this suppression is linked to metabolic deficiencies, specifically the downregulation of lactate dehydrogenase B (LDHB) — an enzyme essential for metabolism and energy production. Follow-up studies demonstrated that LDHB is crucial for pDC-mediated IFN-I production, and its deficiency limits the host’s ability to control viral infections. Remarkably, restoration of LDHB in suppressed pDCs was sufficient to improve their IFN-I production capacity. The extent to which pDCs function depends on — and can be restored by — LDHB expression was a surprising discovery for the research team, highlighting metabolism as a key regulator of this potent interferon-producing cell.
Zúñiga believes that interventions that target LDHB or related metabolic pathways could be explored as a way to counteract the normal cycle of pDC suppression and boost interferons in viral infections and cancers, or to limit the pathogenic production of these proteins in autoimmune diseases.
“We found that defective metabolism is deeply linked to the suppression of pDCs that naturally occurs during a viral infection. This is significant because these cells have an unparalleled capacity to produce interferons, which are essential in antiviral defense and antitumor immunity, while also playing pathogenic roles in autoimmunity” said Zúñiga. “Targeting metabolic pathways such as those related to the enzyme LDHB in these potent interferon-producing cells could empower immune responses against infections and cancer or mitigate pathology in autoimmune diseases.”
The research paper, “Metabolic deficiencies underlie reduced plasmacytoid dendritic cell IFN-1 production following viral infection,” was published on Feb. 7, 2025 in Nature Communications. The full author list includes 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 and Elina I. Zúñiga. Funding for the study was provided by the National Institutes of Health (AI145314, AI132122, AI081923, R50CA252146 and R50CA283813).
A colon histology from virally infected mice that received pDCs.
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