{
  "abstract": "Borrelia burgdorferi, the causative agent of Lyme disease, elicits a robust type I interferon (IFN-I) response that has been strongly associated with chronic inflammatory manifestations such as Lyme arthritis. Although IFN-I is known to be induced early during infection, its functional role in the initial stages of B. burgdorferi infection remains unclear. Here, we identify a protective role for IFN-I signaling in the early control of B. burgdorferi. At 5 days post-challenge, mice lacking the type I interferon receptor (IFNAR1) exhibited markedly elevated spirochetal burdens at the site of inoculation, indicating that IFN-I signaling contributes to restricting early bacterial expansion. By 10 days post-challenge, IFNAR1 deficiency resulted in significantly increased bacterial loads in the skin and a trend toward higher loads in heart tissues, while joint burdens remained unaffected. Mechanistically, IFN-I signaling enhanced macrophage uptake of B. burgdorferi, phagosomal processing, and intracellular killing, while also modulating inflammatory cytokine responses and promoting macrophage recruitment to the inoculation site. Conversely, pharmacological activation of IFN-I signaling augmented macrophage antimicrobial function and improved bacterial clearance. Together, these findings establish IFN-I as a key component of early host defense against B. burgdorferi and reveal a time-dependent role for IFN-I signaling in Lyme disease pathogenesis, with protective functions during early infection that contrast with its pathogenic effects at later stages. Author summary: Lyme disease is caused by the spirochete Borrelia burgdorferi, which is transmitted to humans through the bite of infected ticks. The spirochete must evade the host’s immune defenses to establish infection in the skin, persist, and disseminate to other tissues to cause disease. Type I interferons (IFN-I) are best known for their antiviral roles, but they are also strongly induced during Lyme disease. While IFN-I responses have been linked to the development of Lyme arthritis in later stages of infection, their role during the earliest phase of Lyme disease has remained unclear. In this study, we show that IFN-I signaling plays a protective role early after B. burgdorferi inoculation. Mice lacking the type I interferon receptor (IFNAR1) were unable to efficiently control bacterial growth at the site of inoculation. Mechanistically, IFN-I signaling enhanced the ability of macrophages to engulf, process, and kill B. burgdorferi, promoted inflammatory cytokine production, and supported the recruitment of macrophages to the site of inoculation. Importantly, short-term activation of IFN-I signaling enhanced bacterial clearance, whereas loss of this pathway impaired early immune control. Together, these findings reveal that IFN-I has time-dependent roles during Lyme disease, protecting the host during early-stage infection while contributing to inflammation at later stages. By defining the time-dependent role of IFN-I signaling in Lyme disease, our study advances understanding of how innate immune responses shape infection outcome and highlights potential strategies for enhancing early host defense.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America",
    "Department of Public Health Genomics, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, India"
  ],
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  "author_total": 6,
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        0
      ],
      "name": "Raj Priya"
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    {
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        0,
        1
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      "name": "Sajith Raghunandanan"
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    {
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        0
      ],
      "name": "Darko Mihaljica"
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    {
      "affs": [
        0
      ],
      "name": "Nada S. Alakhras"
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    {
      "affs": [
        0
      ],
      "name": "Mark H. Kaplan"
    },
    {
      "affs": [
        0
      ],
      "name": "X. Frank Yang",
      "orcid": "0000-0002-7231-3167"
    }
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  "doi": "10.1371/journal.ppat.1013996",
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      "heading",
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      "heading",
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  "pmcid": "PMC13722298",
  "pmid": "42932384",
  "published": "2026-10-26",
  "publisher": "Public Library of Science",
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  "subjects": [
    {
      "field": "biology",
      "origin": "plos:cell biology",
      "subfield": "cell-biology"
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    {
      "field": "biology",
      "origin": "heading:Developmental Biology",
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  "title": "Type I interferon signaling promotes early innate control of Borrelia burgdorferi infection",
  "title_text": "Type I interferon signaling promotes early innate control of Borrelia burgdorferi infection",
  "type": "peer-reviewed",
  "updated_at": "2026-11-03T12:22:50Z",
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