Modeling host responses to tick feeding and tick-borne flavivirus evolution and dispersal

Ixodid ticks are hematophagous arthropods that feed on host animals for an extended period of time. To facilitate feeding, ticks secrete a complex mixture of salivary molecules that inhibit host responses such as coagulation, complement, itch responses, and immune responses. Ticks act as vectors for an extremely broad range of human and animal pathogens. Many tick-borne pathogens are significant public health risks throughout the world. In addition, even un-infected ticks cause significant economic losses in the livestock industry. Seminal studies have shown that animals with prior exposure to un-infected ticks can develop an immune response that reduces successful feeding and pathogen transmission by infected ticks in subsequent infestations. Despite the importance of the host response, very few studies have looked at the in vivo response to ticks at the level of the skin. In the following studies, the murine cutaneous response during initial and subsequent infestations with Ixodes scapularis and Dermacentor andersoni nymphs was characterized using PCR-array, microarray, histopathology, and protein-detection methods. These studies show a pro-inflammatory innate-like immune response characterized by cytokines IL-1b, IL-6, IL-10, chemotaxis of neutrophils and monocytes, wound healing responses, anti-microbial peptides, reactive oxygen species, and C-type lectins. Some down-regulation of transcription during primary infestation was indicated. During secondary infestations, these responses intensified and more cell types infiltrated the bite site. A Th2-type response was suggested for D. andersoni but a mixed Th1/Th2 response was suggested for I. scapularis. The host response to I. scapularis was much more activated during primary infestations than that to D. andersoni, possibly because of differences in the mode of tick attachment. Comparison of these host responses to published literature suggests the cutaneous response to ticks can be characterized as a wound healing response. In a final study, a model of tick-borne flavivirus evolution and dispersal was refined. This study suggests that Powassan encephalitis virus has been in North America for about 12,000 years, and that it will become a more significant public health risk as deer and tick populations increase in the United States.