Decoding the Tick Gut‑Immune Axis to Disrupt Circulation of Haemorrhagic Arboviruses

"Tick-borne viruses (TBVs) such as tick-borne encephalitis virus (TBEV) and severe fever with thrombocytopenia syndrome virus (SFTSV) are growing threats for human and animal health, with rising incidence across Europe and Asia due to climate change, vector expansion and globalitasion. Despite their high fatality rates and zoonotic potential, especially for haemorrhagic fever viruses like SFTSV, there are currently no effective strategy to block their transmission from infected tick to vertebrate host. Standard vector control strategies (repellents, prevention) fail to interrupt TBV spread, which occurs rapidly after tick attachment. Addressing this gap requires a shift in focus toward the earliest stages of infection inside the vector itself. My research vision is to dissect virus-tick interactions at the cellular and tissue levels to identify the molecular determinants that govern viral maintenance and dissemination within the tick. Within this framework I propose the TICK-TAC-TOE project (Decoding the Tick Gut‑Immune Axis to Disrupt Circulation of Haemorrhagic Arboviruses). The acronym reflects the dynamic interplay between virus and vector-a strategic molecular game where both sides deploy countermeasures to either evade or reinforce antiviral defenses. TICK-TAC-TOE breaks new ground by focusing on the tick midgut, the very first site of viral entry and replication following ingestion of infected blood. This project aims to uncover how TBVs interact with gut epithelial cells and navigate the gut barrier to establish systemic infection, a process that remains poorly understood and largely overlooked in current research. To inestigate my research question, I will generate the first validated epithelial cell lines and ex vivo gut cultures from two medically important vector species (Ixodes ricinus, Haemaphysalis longicornis) and systematically dissect how immune and stress responses in the midgut epithelium regulate infection. Through a comparative virology approach contrasting TBEV (a flavivirus) and SFTSV (a bunyavirus), it will identify conserved molecular effectors that shape viral replication and vector competence. These insights will provide a mechanistic basis for the development of anti-tick interventions, such as broad-spectrum vaccines targeting gut-specific factors essential for transmission Led by Dr. Marine Petit, a recognized expert in tick virology and systems biology, the project will be hosted at the Ecology and Emergence of Arthropod-borne Pathogens (EEAP) unit at Institut Pasteur, a world-leading center for arbovirus and vector biology. The work is strengthened by strategic international collaborations (Japan, Czechia), cross-disciplinary expertise (virology, tick biology, immunology), and institutional access to tick colonies, BSL-3 labs. A dedicated team including a post-doctoral fellow and a PhD student, alongside Dr. Petit, will execute, a three-tiered experimental framework across cellular, tissue, and organismal levels. This research directly addresses ANRS MIE's mandate to develop tools against emerging and re-emerging arboviruses, especially hemorrhagic fever viruses (volets 1 and 2). By focusing on SFTSV and TBEV, both WHO-priority pathogens with growing geographic overlap, the project tackles a One Health challenge with severe epidemic potential. It establishes foundational tick virology models, identifies molecular biomarkers of infection, and delivers a scalable pipeline for transmission-blocking target discovery, advancing PEPR MIE goals to accelerate translational solutions against emerging infections."