Type I interferon signaling promotes early innate control of Borrelia burgdorferi infection
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 induced early after infection, its functional contribution during the initial stages of B. burgdorferi infection has remained unclear. Here, we identify a critical protective role for IFN-I signaling in the early control of B. burgdorferi. At 5 days post-infection, mice lacking the IFN-I interferon receptor (IFNAR1) exhibited markedly elevated spirochetal burdens at the site of inoculation, indicating that IFN-I is required to restrict early bacterial expansion. By 10 days post-infection, IFNAR1 deficiency resulted in significantly increased bacterial loads in skin and heart tissues, while joint burdens remained unaffected. Mechanistically, IFN-I signaling enhanced macrophage phagocytosis and intracellular killing of B. burgdorferi both in vitro and in vivo, and promoted pro-inflammatory cytokine production and recruitment of innate immune cells to the site of infection. Conversely, pharmacological activation of IFN-I signaling augmented macrophage antimicrobial function and improved bacterial clearance. Together, these findings establish IFN-I as an essential 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 SUMMARYLyme disease is caused by the spirochete Borrelia burgdorferi, which is transmitted to humans through the bite of infected ticks. Soon after infection, the spirochete must evade the hosts early immune defenses in the skin to disseminate to other tissues and 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 interferon signaling plays a critical protective role early after B. burgdorferi infection. Mice lacking the IFN-I interferon receptor were unable to efficiently control bacterial growth at the site of infection and showed increased bacterial dissemination. Mechanistically, IFN-I signaling enhanced the ability of macrophages to engulf and kill B. burgdorferi, promoted inflammatory cytokine production, and supported the recruitment of immune cells to the site of infection. 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 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.