Ixodes species ticks are competent vectors of tick-borne viruses including 
tick-borne encephalitis and Powassan encephalitis. Tick saliva has been shown to 
facilitate and enhance viral infection. This likely occurs by saliva-mediated 
modulation of host responses into patterns favorable for viral infection and 
dissemination. Because of the rapid kinetics of tick-borne viral transmission, 
this modulation must occur as early as tick attachment and initiation of 
feeding. In this study, cutaneous bite-site lesions were analyzed using 
Affymetrix mouse genome 430A 2.0 arrays and histopathology at 1, 3, 6, and 12 
hours after uninfected Ixodes scapularis nymphal tick attachment. At 1 and 3 hrs 
after attachment, the gene expression profile is markedly different than at 
later time points. Upregulated gene ontology term clusters enriched at 1 and 3 
hrs were related to post-translational modification. At 6 and 12 hrs, 
cytoskeletal rearrangements, DNA replication/cell division, inflammation, and 
chemotaxis were prominent clusters. At 6 and 12 hrs, extracellular matrix, 
signaling, and DNA binding clusters were downregulated. Histopathological 
analysis shows minimal inflammation at 1 and 3 hrs but an appreciable neutrophil 
infiltrate at 6 and 12 hrs. In addition, putative hyperemia, localized necrosis, 
and increased ECM deposition were identified. Putting the gene expression and 
histopathology analysis together suggests early tick feeding is characterized by 
modulation of host responses in resident cells that merges into a nascent, 
neutrophil-driven immune response by 12 hrs post-attachment.