LRP8-dependent neurotropism of tick-borne encephalitis virus: From species-specific entry gateway to zoonotic spillover and receptor-mimetic therapy
Tick-borne encephalitis virus (TBEV), a neurotropic flavivirus, is the causative agent of tick-borne encephalitis (TBE), a severe and potentially fatal central nervous system infection. TBEV is maintained in an enzootic cycle involving Ixodes ticks and vertebrate reservoirs, with small mammals serving as primary amplifying hosts and ungulates supporting tick population expansion. From this foundational cycle, the virus extends its reach through ticks to infect a broader host range—including larger mammals, birds, and reptiles—thereby creating additional pathways for spillover into human populations.1 While the primary threat to humans comes from infected tick bites, transmission can also occur through non-vectorial means, such as consuming unpasteurized dairy products.
The incidence of TBE has shown a consistent upward trend in recent decades, especially across European nations including Estonia, Finland, Italy, and Poland. From 2015 to 2020, reported cases rose from 0.4 to 0.9 per 100,000 individuals, with the highest incidence rates recorded in Baltic and Central European regions.2 This increase is related to climate change, land-use shifts, and alterations in wildlife host populations—factors that are reshaping vector-host dynamics and promoting the spread of TBEV into areas previously considered non-endemic. In particular, urban expansion—encompassing land reclamation and forest exploitation—has facilitated human encroachment into tick habitats. These interconnected factors are intensifying human-tick interactions, thereby elevating the risk of TBEV transmission to humans against the backdrop of ongoing economic development and urbanization.3 Notwithstanding the existence of effective TBEV vaccines, suboptimal immunization rates in endemic countries and the lack of specific antiviral therapies necessitate the urgent development of innovative control strategies. As viruses need to bind the cells’ proteins to gain entry and start infection, uncovering receptors essential for TBEV infection is imperative for advancing our understanding of TBEV-induced neuropathogenesis, the diversity of viral host ranges, and the discovery of novel therapeutic targets.
The study by Mittler et al. constitutes a significant contribution to the field,4 enhancing our comprehension of TBEV pathogenesis and laying the groundwork for innovative therapeutic approaches. Utilizing a genome-wide CRISPR screen, the researchers uniquely pinpointed LRP8 as a leading candidate. Functional studies definitively established LRP8’s causal role in mediating TBEV cellular entry. The specificity of LRP8 for TBEV distinguishes it from other known receptors, as it is not employed by other tested orthoflaviviruses for host cell invasion, positioning LRP8 as a defining factor in TBEV’s cellular tropism. Subsequently, it was observed that LRP8 specifically binds the TBEV envelope (E) protein. This interaction was meticulously mapped to the LA1–2 domains of LRP8 and the DIII of the E protein, confirming its identity as a bona fide receptor-ligand pair. Consequently, these interactions facilitate the initial attachment of TBEV particles to the cell surface and promote their subsequent internalization via the endocytic pathway.
