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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE286962 | GEO | 2025/01/14

REPOSITORIES: GEO

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Project description:Introduction: Ixodes scapularis ticks are hematophagous arthropods capable of transmitting many infectious agents to humans. The process of blood feeding is an extended and continuous interplay between tick and host responses. While this process has been studied extensively in vitro, no global understanding of the host response to ticks has emerged. To address this issue, we measured skin-specific expression of 233 discrete genes at 8 time points during primary and secondary infestations of mice with pathogen-free I. scapularis nymphs. Selected results were then validated at the mRNA and protein levels. Results: Primary infestation was characterized by the late induction of an innate immune response. Lectin pattern recognition receptors, cytokines, and chemokines were upregulated consistent with increased neutrophil and macrophage migration. Gene ontology and pathway analyses of downregulated genes suggested inhibition of gene transcription and Th17 immunity. During the secondary infestation, additional genes were modulated suggesting a broader involvement of immune cells including CD8 and CD4 positive T lymphocytes. The cytokine response showed a mixed Th1/Th2 profile with a potential for T regulatory cell activity. Key gene ontology clusters observed during the secondary infestation were cell migration and activation. Matrix metalloproteinases were upregulated, apoptosis-related genes were differentially modulated, and immunoreceptor signaling molecules were upregulated. In contrast, transcripts related to mitogenic, WNT, Hedgehog, and stress pathways were downregulated. Conclusions: Our results support a model of tick feeding where lectin pattern recognition receptors orchestrate an innate inflammatory response during primary infestation that primes a mixed Th1/Th2 response upon secondary exposure. Tick feeding inhibits gene transcription and Th17 immunity. Salivary molecules may also inhibit upregulation of mitogenic, WNT, Hedgehog, and stress pathways and enhance the activity of T regulatory cells, production of IL-10, and suppressors of cytokine signaling molecules (SOCS). This study provides the first comprehensive transcriptional analysis of the host response at the tick bite site and suggests both a potential model of the host cutaneous response and candidate genes for further description and investigation. Ear biopsies from BALB/cJ mice infested with Ixodes scapularis nymphs were assayed at 12, 48, 72, and 96 hours after infestation during a primary and secondary exposure. 3 mice were measured at each time point. Controls were 3 similarly housed but tick-free mice.

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

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