Tick extracellular vesicles undermine epidermal wound healing during hematophagy
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Abstract
Wound healing has been extensively studied through the lens of inflammatory disorders and cancer, but limited attention has been given to hematophagy and arthropod-borne diseases. Hematophagous ectoparasites, including ticks, subvert the wound healing response to maintain prolonged attachment and facilitate blood-feeding. Here, we unveil a strategy by which extracellular vesicles (EVs) ensure blood-feeding and arthropod survival in three medically relevant tick species. We demonstrate through single cell RNA sequencing and murine genetics that wildtype animals infested with EV-deficient Ixodes scapularis display a unique population of keratinocytes with an overrepresentation of pathways connected to wound healing. Tick feeding affected keratinocyte proliferation in a density-dependent manner, which relied on EVs and dendritic epidermal T cells (DETCs). This occurrence was linked to phosphoinositide 3-kinase activity, keratinocyte growth factor (KGF) and transforming growth factor β (TGF-β) levels. Collectively, we uncovered a strategy employed by a blood-feeding arthropod that impairs the integrity of the epithelial barrier, contributing to ectoparasite fitness.
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We haven't done any of these experiments beyond day 3. Part of the problem is related to the technical challenges associated with those experiments. It would be very difficult to obtain any statistical power and increase the scientific rigor of the manuscript.
Having said that, it is entirely possible that the DETC effect goes away after 3 days and/or before 3 days. Tick saliva changes overtime (tick feeding) and the effect may occur in a DETC-independent manner. It is a limitation of our study. Hope it helps.
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Collectively, these findings provided evidence that tick EVs functionally regulate DETCs in the murine skin
Beautifully written paper!
Regarding the EVs' regulation of DETCs: how long does the effect last? If you allowed the ticks to feed for 3 days, then removed them and waited another 48 hours before taking the biopsies... do you expect the DETCs would still show impaired rounding?
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Hi Rachel,
Thanks for reaching out. We think this uncharacterized population is specific to tick EVs, as we silenced Vamp33, which is involved in tick EV biogenesis and got this phenotype. We have some correlative evidence suggesting that tick EVs are specifically inhibiting keratinocyte proliferation.
Nevertheless, we are testing some of the biological circuits involved in this process through CRE mice in keratinocytes. In the CRE-mouse validations, we will do a head-to-head comparison with standard wound healing assays (i.e., scratch assay) to obtain causation.
As to the identification of specific tick salivary proteins that are affecting the process in vivo, this is certainly a more difficult question. Tick salivary proteins tend to work redundantly at physiological concentrations in vivo (PMID: 26830726). Thus, likely, we will have …
Hi Rachel,
Thanks for reaching out. We think this uncharacterized population is specific to tick EVs, as we silenced Vamp33, which is involved in tick EV biogenesis and got this phenotype. We have some correlative evidence suggesting that tick EVs are specifically inhibiting keratinocyte proliferation.
Nevertheless, we are testing some of the biological circuits involved in this process through CRE mice in keratinocytes. In the CRE-mouse validations, we will do a head-to-head comparison with standard wound healing assays (i.e., scratch assay) to obtain causation.
As to the identification of specific tick salivary proteins that are affecting the process in vivo, this is certainly a more difficult question. Tick salivary proteins tend to work redundantly at physiological concentrations in vivo (PMID: 26830726). Thus, likely, we will have several proteins acting on this process, perhaps, being transported as a cargo inside EVs. It is almost impossible to address this question in vivo, although it can certainly be done in vitro through non-physiological concentrations using a tour de force (again, see PMID: 26830726).
I hope it helps. I will be happy to continue our discussion. Please reach out if needed. Joe
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we observed an unidentified keratinocyte population found solely when EV-deficient ticks fed on FVB-Jax mice
Congrats on this study - it is super interesting! One thing I was wondering is whether this unidentified keratinocyte population is specifically stimulated by tick bites (potentially through detection of some other salivary molecule?), or whether is would be found in any example of injury (and thus a normal population involved in would healing)?
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