From Local to Systemic: The Journey of Tick Bite Biomarkers in Australian patients.

Tick bites and tick-related diseases are on the rise. Diagnostic tests that identify well-characterised tick-borne pathogens (TBPs) possess limited capacity to address the causation of symptoms asso-ciated with poorly characterised tick-related illnesses, such as debilitating symptom complexes attributed to ticks (DSCATT) in Australia. Identification of local signals in tick-bitten skin that can be detected systemically in blood would have both clinical (diagnostic or prognostic) and research (mechanistic insight) utility, as a blood sample is more readily obtainable than tissue biopsies. We hypothesised that blood samples may reveal signals which reflect relevant local (tissue) events, and that the time course of these signals may align with local pathophysiology. As a first step to-wards testing this hypothesis, we contrasted molecular signatures in skin biopsies taken from the tick-bite location of human participants along with peripheral blood signatures obtained at the same time. This approach captures differentially expressed molecules across multiple omics da-tasets derived from peripheral blood (including cellular and cell-free transcriptomics, proteomics, metabolomics, and DNA methylation), and skin biopsies (spatial transcriptomics). Our data re-vealed that extracellular matrix organisation and platelet degranulation pathways were upregu-lated in skin within 72 hours of a tick bite. The same signals appeared in blood, where they then remained elevated for three months, displaying longitudinally consistent alterations of biological functions. Despite the limited sample size these data represent proof-of-concept that molecular events in the skin following a tick bite can be detectable systemically. This underscores the poten-tial value of blood samples, akin to liquid biopsy, to capture biomarkers reflecting local tissue processes.