The Development of Encephalitis Following Tick-Borne Encephalitis Virus Infection in a Mouse Model

Tick-borne encephalitis virus (TBEV) belongs to the genus Flavivirus in the family Flaviviridae. TBEV is transmitted through the bite of an infected tick and causes acute central nervous system (CNS) disease in humans (Dumpis, Crook, and Oksi, 1999; Lindquist and Vapalahti, 2008). TBEV is prevalent over a wide area of Europe and Asia, and is geographically and genetically divided into three subtypes, the European, Siberian and far eastern subtypes (Ecker et al., 1999; Hayasaka et al., 2001b). The endemic areas of Europe and Asia correspond to the geographical distribution of Ixodes tick species (Burke and Monath, 2001; Dumpis, Crook, and Oksi, 1999). Tick-borne encephalitis (TBE) cases exhibit neurological symptoms including fever, headache, meningitis, meningoencephalitis and meningoencephalomyelitis, the latter being evident in the most severe cases (Dumpis, Crook, and Oksi, 1999). These non-specific clinical features of TBE may be due to widespread occurrence of neuronal dysfunction at different sites in the CNS. Hence, laboratory diagnosis is required to distinguish TBE from other neurological disorders (Charrel et al., 2004; Holzmann, 2003). The laboratory mouse model is commonly employed to elucidate the mechanism of disease development following TBEV infection in vivo. The pathogenetic process following experimental infection with TBEV is fundamentally similar to that of other encephalitic flaviviruses including Japanese encephalitis virus (JEV), West Nile virus (WNV) and Murray Valley encephalitis virus (MVEV) (Albrecht, 1968; Burke and Monath, 2001; Garcia-Tapia et al., 2007). In the mouse model, the CNS pathology of TBEV and other encephalitic flaviviruses consists of two distinct features: neuroinvasiveness and neurovirulence. It is generally considered that death following peripheral infection represents neuroinvasiveness, whereas mortality following direct intracerebral infection represents neurovirulence (Mandl, 2005; Monath, 1986). Recent works have proposed that CNS pathology following TBEV infection is a consequence of viral infection of the corresponding cells and the resulting inflammatory response. Direct viral infection of neurons is considered to be the major cause of neurological disease because viral infections cause apoptosis or degeneration of neurons in vivo and in vitro (Couderc et al., 2002; Liao et al., 1997; Prikhod'ko et al., 2001; Shrestha, Gottlieb, and Diamond, 2003). In addition, recent studies have demonstrated that immunopathological effects also contribute to the severity of CNS pathology (Hayasaka et al., 2009; Ruzek et al., 2009; Wang et al., 2003).