A systems biology approach to Australian tick-borne disease

Wenna L Lee

Tick-borne diseases (TBDs) are a growing global health concern as ill-defined tick-associated pathologies remain with unknown aetiologies despite extensive studies. Tick bites often elude notice and human responses after tick-bite and inter-individual variations of response phenotypes are not well characterised. Current reductive, pathogen-centric methodologies limit our understanding of more complex tick-associated illness, which results from the interactions between the host, tick, and microbes. It is posited that examining the skin at the focal point of a tick bite could reveal molecular signatures, potentially bridging the existing gap and aiding in the exploration of prospective prognostic or therapeutic biomarkers. As an initial step toward that objective, a pilot study was planned to investigate the feasibility and informativeness of such an approach using samples collected from five tick-bitten patients enrolled with 72 hours of tick bite during the 2021/2022 tick season in Western Australia. The overall aims of this research were to i) analyse participants’ paired skin biopsies for local spatially resolved signatures; ii) analyse participants’ systemic blood omics signatures individually; iii) perform a multi-omics integration of blood omics signature; iv) and to perform a correlation study between tick-bitten participants’ local signatures (in the skin biopsies) with systemic (peripheral blood) signatures. The first aim utilised spatial transcriptomics on skin tissues from tick-bitten samples (cases) vs contralateral samples (controls) collected at the same time from the same participants, to detect local tick bite- specific signatures. The data could differentiate signatures from tick-bitten and contralateral control skin as well as discern a pattern of signatures common with the main cohort when compared to a participant sampled three months post tick bite. For aims two and three, peripheral blood samples collected from the same participants, over three timepoints, were interrogated in a pair-wise manner across various omics disciplines, including transcriptomics (both cellular and cell-free), proteomics, metabolomics, and epigenetic methylation, first in a univariate manner and subsequently integrated via DIABLO, a supervised sparse projection to latent structures - determinant analysis (sPLS-DA) based method. The utility of the proteomics dataset was demonstrated here to be particularly promising with perturbations differentiating all timepoints. The multi-omics integration of data selected variables across omics datasets that were discriminative of timepoints and revealed unexpected potential biological insight. Finally, for aim four, the signatures uncovered over the preceding three aims were compared to investigate the potential of peripheral blood markers as surrogate markers for the local signatures of tick bites, revealing various similarities that can be validated in larger studies. Many symptomatic tick-bite patients unfortunately receive ‘normal’ test results with conventional diagnostic tests for TBDs. Despite a small pilot cohort of five participants, the data in this PhD thesis demonstrated that a wealth of host-mediated molecular signals dwell in various biological samples. The analysis pipelines developed in this thesis can be scaled to include a larger cohort to provide interpretable biological insights and more avenues of analysis that might explain the lived experiences of symptomatic tick-bitten humans.

A systems biology approach to Australian tick-borne disease

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