During cutaneous tick attachment, the feeding cavity becomes a site of transmission for tick salivary compounds and tick-borne pathogens. However, the immunological consequences of tick feeding on human skin remain unclear. Here, we assessed human skin and blood samples upon tick bite and developed a human skin explant model mimicking Ixodes ricinus bite and tick-borne pathogen infection. Following tick attachment, we observed rapidly occurring patterns of immunomodulation including increase in neutrophils and cutaneous B and T cells. T cells up-regulated tissue-residency markers, while lymphocytic cytokine production was impaired.In early stages of Borrelia burgdorferi model infections, we detected strain-specific immune responses and close spatial relationships of macrophages and spirochetes. Pre-incubation of spirochetes with tick salivary gland extracts hampered accumulation of immune cells and increased spirochete loads. Collectively, we showed 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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