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.