Abstract
Emerging and re-emerging diseases transmitted by blood feeding arthropods are significant global public health problems. Ticks transmit the greatest variety of pathogenic microorganisms of any blood feeding arthropod. Infectious agents transmitted by ticks are delivered to the vertebrate host together with saliva at the bite site. Tick salivary glands produce complex cocktails of bioactive molecules that facilitate blood feeding and pathogen transmission by modulating host hemostasis, pain/itch responses, wound healing, and both innate and adaptive immunity. In this study, we utilized Illumina Next Generation Sequencing to characterize the transcriptional immunoprofile of cutaneous immune responses to Ixodes ricinus transmitted tick-borne encephalitis virus (TBEV). A comparative immune gene expression analysis of TBEV-infected and uninfected tick feeding sites was performed. Our analysis reveals that ticks create an inflammatory environment at the bite site during the first 3 h of feeding, and significant differences in host responses were observed between TBEV-infected and uninfected tick feeding. Gene-expression analysis reveals modulation of inflammatory genes after 1 and 3 h of TBEV-infected tick feeding. Transcriptional levels of genes specific to chemokines and cytokines indicated a neutrophil-dominated immune response. Immunohistochemistry of the tick feeding site revealed that mononuclear phagocytes and fibroblasts are the primary target cells for TBEV infection and did not detect TBEV antigens in neutrophils. Together, the transcriptional and immunohistochemistry results suggest that early cutaneous host responses to TBEV-infected tick feeding are more inflammatory than expected and highlight the importance of inflammatory chemokine and cytokine pathways in tick-borne flavivirus transmission.
Highlights
Tick-borne encephalitis virus (TBEV) is a zoonotic tick-borne virus in the Flaviviridae family
An online tool (Oliveros, 2007) was used to generate a Venn diagram showing the overlap of significantly modulated genes between the 1 and 3 h comparison of the TBEVinfected vs. uninfected tick feeding sites (Figure 1C). 10.2% of significantly modulated genes were shared between the three comparisons; the majority of significantly modulated genes were unique to either the 1 h tick-borne encephalitis virus (TBEV)-infected vs. 1 h uninfected tick feeding site (18.7%), the 3 h TBEV-infected vs. 3 h uninfected tick feeding site (25.7%), or the 3 h TBEV-infected vs. 1 h TBEV-infected tick feeding site (14%)
A list of all modulated genes at either time point in the study was used to generate a heat map (Figure 1D). This heat map suggests that after 1 h of TBEV-infected tick feeding, there was a pattern of mostly upregulated cutaneous genes; after 3 h, the pattern changed to downregulation
Summary
Tick-borne encephalitis virus (TBEV) is a zoonotic tick-borne virus in the Flaviviridae family (genus Flavivirus). It is the causative agent of tick-borne encephalitis (TBE), a serious neurological disease in humans. The various strains of TBEV are subdivided into three main subtypes that are closely related genetically and antigenically: European (Eu), Siberian (Sib), and Far-Eastern (FE) (Gritsun et al, 2003a; Mansfield et al, 2009). TBEV-FE is present in Far-Eastern Russia and parts of China, Japan, and the Republic of Korea (Mansfield et al, 2009). Human infections with TBEV can range from mild flu-like symptoms to severe or fatal neuroinvasive disease, often with long-term neurological symptoms. The incidence rates vary from year to year and between subtypes, several thousand human TBE cases are reported annually (CDC Tick-borne Encephalitis, 2017)
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