The tick saliva peptide HIDfsin2 promotes the tick-borne virus SFTSV replication in vitro by enhancing p38 signal pathway

Pathogens co-evolved with ticks to facilitate blood collection and pathogen transmission. Although tick saliva was recently found to be rich in bioactive peptides, it is still elusive which saliva peptide promotes virus transmission and which pathways are invovled. Here, we used a saliva peptide HIDfsin2 and a severe fever with thrombocytopenia syndrome virus (SFTSV) both carried by the tick Haemaphysalis longicornis to elucidate the relationship between tick saliva components and tick-borne viruses. HIDfsin2 was found to promote the replication of SFTSV in a dose-dependent manner in vitro. HIDfsin2 was further revealed to MKK3/6-dependently magnify the activation of p38 MAPK. The overexpression, knockdown and phosphorylation site mutation of p38α indicated that p38 MAPK activation facilitated SFTSV infection in A549 cells. Moreover, the blockade of p38 MAPK activation significantly suppressed SFTSV replication. Differently, HIDfsin2 or pharmacological inhibition of p38 MAPK activation had no effect on a mosquito-borne Zika virus (ZIKV). All these results showed that HIDfsin2 specifically promoted SFTSV replication through the MKK3/6-dependent enhancement of p38 MAPK activation. Our study provides a new perspective on the transmission of tick-borne viruses under natural conditions, and supports that the blockade of p38 MAPK activation can be a promising strategy against the mortal tick-borne virus SFTSV.