Acquired tick resistance is a phenomenon wherein the host elicits an immune response against tick salivary components upon repeated tick infestations. The immune responses, potentially directed against critical salivary components, thwart tick feeding, and the animal becomes resistant to subsequent tick infestations. The development of tick resistance is frequently observed when ticks feed on non-natural hosts, but not on natural hosts. The molecular mechanisms that lead to the development of tick resistance are not fully understood, and both host and tick factors are invoked in this phenomenon. Advances in molecular tools to address the host and the tick are beginning to reveal new insights into this phenomenon and to uncover a deeper understanding of the fundamental biology of tick-host interactions. This review will focus on the expanding understanding of acquired tick resistance and highlight the impact of this understanding on anti-tick vaccine development efforts.

Despite broad appreciation of their clinical utility, it has been unclear how vitamin B12 and folic acid (FA) function at the molecular level to directly prevent their hallmark symptoms of deficiency like anemia or birth defects. To this point, B12 and FA have largely been studied as cofactors for enzymes in the one-carbon (1C) cycle in facilitating the de novo generation of nucleotides and methylation of DNA and protein. Here, we report that B12 and FA function as natural antagonists of aryl hydrocarbon receptor (AhR). Our studies indicate that B12 and FA bind AhR directly as competitive antagonists, blocking AhR nuclear localization, XRE binding, and target gene induction mediated by AhR agonists like 2,3,7,8-tetrachlorodibenzodioxin (TCDD) and 6-formylindolo[3,2-b]carbazole (FICZ). In mice, TCDD treatment replicated many of the hallmark symptoms of B12/FA deficiency and cotreatment with aryl hydrocarbon portions of B12/FA rescued mice from these toxic effects. Moreover, we found that B12/FA deficiency in mice induces AhR transcriptional activity and accumulation of erythroid progenitors and that it may do so in an AhR-dependent fashion. Consistent with these results, we observed that human cancer samples with deficient B12/FA uptake demonstrated higher transcription of AhR target genes and lower transcription of pathways implicated in birth defects. In contrast, there was no significant difference observed between samples with mutated and intact 1C cycle proteins. Thus, we propose a model in which B12 and FA blunt the effect of natural AhR agonists at baseline to prevent the symptoms that arise with AhR overactivation.