<i>Peromyscus leucopus</i> , <i>Mus musculus</i> , and humans have distinct transcriptomic responses to larval <i>Ixodes scapularis</i> bites

<i>Ixodes scapularis</i> ticks are an important vector for at least seven tick-borne human pathogens, including a North American Lyme disease spirochete, <i>Borrelia burgdorferi</i>. The ability for these ticks to survive in nature is credited, in part, to their ability to feed on a variety of hosts without triggering an immune response capable of preventing tick feeding. While the ability of nymphal ticks to feed on a variety of hosts has been well documented, the host-parasite interactions between larval <i>I. scapularis</i> and different vertebrate hosts are relatively unexplored. Here we report on the changes in the vertebrate host transcriptome present at the larval tick bite site using the natural <i>I. scapularis</i> host <i>Peromyscus leucopus</i>, a non-natural rodent host, <i>Mus musculus</i> (BALB/c), and humans. We note substantially less evidence of activation of canonical proinflammatory pathways in <i>P. leucopus</i> compared to BALB/c mice and pronounced evidence of inflammation in humans. Pathway enrichment analyses revealed a particularly strong signature of interferon gamma, tumor necrosis factor, and interleukin 1 signaling at the BALB/c and human tick bite sites. We also note that bite sites on BALB/c mice and humans, but not deer mice, show activation of wound-healing pathways. These data provide molecular evidence of the coevolution between larval <i>I. scapularis</i> and <i>P. leucopus</i> and, in addition, expand our overall understanding of <i>I. scapularis</i> feeding.