As a consequence of global temperature rise, ticks (Ixodida) and tick-borne diseases are emerging. During tick attachment to human skin, the feeding cavity becomes a site of transmission for tick salivary compounds, which can exert immunosuppressive effects. Tick-borne pathogens including Borrelia burgdorferi may benefit from dampened immune activation at the bite site. We therefore assessed local and circulating human immune cells and cytokine secretion upon tick bite and developed a human skin explant model mimicking Ixodes ricinus bite. Analysis of tick feeding sites revealed a rapidly occurring pattern of immunomodulation in human skin. Neutrophil, B and T cell populations increased, suggesting an initial inflammatory response independent from pathogen transmission. We observed higher expression of T cell tissue-residency markers following tick bite, whereas T cell and innate lymphoid cell cytokine production was stunted. Furthermore, tick bite biopsies contained decreased numbers of dermal dendritic cells and Langerhans cells. In our explant model, local immunomodulation was replicated upon injection of tick salivary gland extracts with and without B. burgdorferi spirochetes. In early stages of B. burgdorferi model infections, we detected strain-specific immune responses and close spatial relationships of macrophages and spirochetes. Importantly, pre-incubation of spirochetes with tick salivary gland extracts hampered local accumulation of immune cells and increases spirochete loads. Collectively, we show that tick feeding exerts profound changes on the skin immune network, which interfere with the primary response against tick-borne pathogens.
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