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 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.