OBJECTS: Vector ticks' perception of characteristic odors emitted by infected hosts is key to understand tick's foraging behavior for infected host and design odor-based control strategies for tick-borne diseases. METHODS: Laboratory mice knocked out for type I interferon (IFN) receptors (Ifnar-/-) were used to develop a simulated host by intraperitoneal infection with Bandavirus dabieense (SFTSV). Urine and fecal samples were collected 4 days post-infection and analyzed to detect differential volatile metabolites (DVMs) during infection. Next, the two salient odor cues among the SFTSV-induced host DVMs, indole and 3-methylindole, were used to test the olfactory response of Haemaphysalis. longicornis by electroantennographic detection (EAD) and Y-tube olfactometry, respectively. To gain insight into the potential olfactory mechanism, two olfactory-associated proteins, Niemann-Pick type C2 (NPC2) and Odor Binding Protein-like (OBPL) proteins were annotated from the transcriptomic data derived from H. longicornis forelegs. Online tools were used to predict the ligand binding properties of the two proteins to the two indole candidates. Simultaneously, quantitative RT-PCR using β-actin as an internal reference gene was used to monitor the relative transcript levels of NPC2 and OBPL proteins under the stimulation of two indole candidates. The significantly regulated proteins were cloned and expressed with the vector plasmid pET-28b in vitro. The purified proteins were tested for the binding properties to the two indole candidates. RESULTS: SFTSV-infected Ifnar-/- mice upregulated 11 DVMs in fecal samples, mostly indoles and phenols, along with indole biosynthesis and related metabolic processes. In the urine samples, 29 DVMs were downregulated in the infected host, with eucalyptol and phenylalanine acid being the most altered. We test the olfactory responses of H. longicornis to indole and 3-methylindole, which influence tick foraging behavior. The olfactometers showed that the tick preferred both indole and 3-methylindole. EAD tests showed that stimulation of the olfactory receptor neuron in Haller's organ produced significant active potential in response to indoles. Two olfactory proteins, NPC2 and OBPL, were successfully annotated from H. longicornis foreleg transcriptomic data. NPC2 has a β-barrel structure that binds signal chemicals, while OBPL is a classical OBP with a hydrophobic binding cavity. When monitoring the transcript levels of NPC2 and OBPL in the tick forelegs, the increased transcript level (1.2-1.4 folds change) of OBPL was observed following indoles stimulation, compared to the downregulated level (0.6-0.8 folds change) of NPC2 under the same circumstances. The OBPL and NPC2 gene from H. longicornis were successfully cloned and expressed as inclusion proteins respectively. The purified OBPL (20.28 kDa) showed higher affinity for both indole (Ki 2.256μM) and 3-methylindole (Ki 4.191μM) than NPC2 in the competitive fluorescence binding assays with 1-NPN as a competitor. CONCLUSIONS: Facilitated by the olfactory OBPL protein in Haller's organ, H. longicornis smells and is attracted to the characteristic indolic scents of hosts induced by SFTSV infection. Olfactory associations between infected hosts and vector arthropods could provide a new perspective to understand host foraging behavior and design novel control strategies for tick-borne diseases based on pathogen-induced scent according to chemical ecology theory.