The effect of tick saliva on cellular stress responses and its implication to tick-borne encephalitis virus transmission


Ticks are vectors of many medically important pathogens including Borrelia spirochets or tick-borne encephalitis virus (TBEV). Transmission of these pathogens occurs following the bite of an infected tick. Ticks release its saliva during feeding into feeding pool and that not only ensure proper condition for ticks to feed for several days but also support transmission of tick borne pathogens into the host. This process is called saliva assisted transmission or SAT. Numerous pharmacologically active molecules present in tick saliva are able to modulate host defenses, including wound healing, haemostasis, inflammation, innate and adaptive immunity (Fig.1).

 

Skin resident cells, including dendritic cells and macrophages are among first cells to interact with tick transmitted pathogens. Therefore we focus on DC and macrophages, though our interest is not limited only to these cells. DC and macrophages in addition to its immune function are also susceptible to TBEV replication which means that they can represent another source of virus particles which spread within the host. The immunomodulation of DC induced by tick saliva include the inhibition of cell maturation, migration, production of pro-inflammatory and decrease in antigen presentation. The underlying mechanism of this immunomodulation was intensively studied. We identified several signaling pathways which were affected by tick saliva and by tick salivary cysteine inhibitors in borrelia- exposed DC (Fig.2).

 

Currently we investigate the mechanism of saliva assisted transmission related to TBEV infection. We found that components of tick saliva enhance the activation of pro-survival Akt pathway in TBEV-infected dendritic cells (Fig. 3a) and also increase TBEV replication (Fig. 3b).

 

We hypothesize that tick saliva facilitates TBEV transmission by inhibiting cellular stress pathways which are regulated by Akt and activated upon tick bite or virus infection. Stress cellular pathways include DAMP-triggered signaling, oxidative stress and endoplasmic reticulum stress responses and serve to prime cells to adequately respond to pathogens thus influencing the development of immune response and inflammation. Stress also affects biogenesis and release of exosomes, vesicles recently described to be involved TBE virus transmission. The impact of tick saliva on exosome formation is being investigated.