Factors in the environment, viruses and host responses affecting the epidemiology of tick-borne encephalitis virus in Northern Europe

Abstract: Tick-borne encephalitis virus (TBEV) circulates mainly in the Ixodes ricinus and Ixodes persulcatus tick species, which serve both as hosts and vectors for the virus. Wild rodents are considered as bridges for non-viremic transmission between the ticks, which is the most important maintenance factor for TBEV. Secondary hosts support TBEV circulation as bloodmeal sources for ticks. The fragile maintenance cycle of the virus is affected by climates and availability of biotic factors thus, TBEV is found only in restricted foci by the Baltic Sea and the biggest lakes in Finland. TBEV is transmitted to humans when bitten by an infected tick. Infection may lead to a clinical disease, tick-borne encephalitis (TBE). The number of TBE cases has increased in Europe since the 1980s. Disease manifestation ranges from mild flu-like illness to inflammation of the central nervous system (CNS), and is in some cases followed by severe quality-of-life impairing sequelae. The clinical picture varies according to the virus subtype, as well as the age and genetic background of the patient. Three subtypes of TBEV are known: European (TBEV-Eur), Siberia (TBEV-Sib) and Far-Eastern (TBEV-FE). TBEV-Eur is carried mainly by I. ricinus and the two latter subtypes by I. persulcatus. Finland lies in the mixing zone of the tick species as both of the main host tick species and two of the three TBEV subtypes, TBEV-Eur and TBEV-Sib, are endemic in Finland. The disease has been known in Åland islands since the 1950s as Kumlinge disease. Also the south-western archipelago and the Lappeenranta region by Lake Saimaa waterway in South-Eastern Finland have been known to be endemic for decades. TBE is a notifiable disease in Finland. All laboratory diagnosed cases are reported to the Institute of Health and Welfare by the treating hospital district, often the one of the municipality of residence of the patient. In the present study we surveyed all human cases reported in Finland during 2007-2013 by the geographical place of infection. We also surveyed the diagnostic alertness for TBE in different hospital districts in Finland and among patients with neurological infections with unknown aetiology. The number of suspected patients with TBE doubled during the period of our survey from 563 to 1154. However, TBE was not significantly underdiagnosed among patients with neurological infections with unknown aetiology. Besides the previously known endemic areas, infections were reported in a wider region around Saimaa, in central Finland and at the coast of Gulf of Finland. The areas with repeated human TBE cases were found in the northern part of the west coast, north of 64° latitude. We studied further in more detail several geographical sites of human infections. In Simo, Finnish Lapland the major tick species was I. persulcatus, as is expected in the north, but it unexpectedly carried the TBEV-Eur subtype. Therefore, we suggest that tick species in the area is not preventative for establishment of any newly introduced TBEV-subtype. Also, the species distribution of small mammals at the geographical sites of human infections was studied. While Apodemus mice are considered the most important hosts for TBEV maintenance in the deciduous zone, the bank vole, Myodes glareolus was the dominant species in the sites studied in Finland. An exception was the island Isosaari in Helsinki, where the vole species was exclusively Microtus agrestis, the field vole. To further study the infection kinetics and persistence of TBEV in the natural host species in the boreal zone as well as to compare the TBEV subtypes, we infected colonized bank voles with strains representing each of the three known TBEV subtypes. All strains were infective and highly neurotropic. TBEV-RNA could be detected in the brain as long as 168 days post infection. Clearance of TBEV-RNA from the brain was significantly slower than from the other organs investigated. However, attempts to show infectivity in cell culture were not successful. TBEV-FE induced prolonged viremia, indicating that its kinetics in rodents may differ from that of the other two subtypes. Altogether, the study showed that bank voles can develop TBEV infection of the CNS with inflammation and other pathological findings comparable with encephalitis. However, clinical symptoms were seen only in a few individuals and thus bank voles can serve as resistant models for studies on tick-borne encephalitis. Persistence of viral RNA in the brain of animals with asymptomatic course of infection supported our findings in wild rodents: TBEV-RNA was detectable in the brain of bank voles and field voles in winter several months after tick-feeding season in both TBEV-Sib and TBEV-Eur endemic areas (Kokkola and Isosaari, respectively). It is unlikely, that the individuals would have survived until February and March having manifested symptoms or impaired functional abilities. Serological analyses on wild rodents and laboratory animals support the suggestion that rodents may serve as sentinels for TBEV endemicity. However, the detection method, target organ, trapping season, sentinel species, and ecological parameters of the trapping site should be considered carefully when interpreting the results.