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1 Vantaa Research Unit, Finnish Forest Research Institute, PO Box 18, FIN-01301 Vantaa, Finland
2 Department of Biological and Environmental Science, PO Box 35, FIN-40014 University of Jyväskylä, Finland
3 Swedish Institute for Infectious Disease Control, SE-171 82 Solna, Sweden
4 Microbiology and Tumor Biology Center, Karolinska Institutet, SE-171 77 Stockholm, Sweden
5 Department of Basic Veterinary Sciences, Faculty of Veterinary Medicine, University of Helsinki, PO Box 66, FIN-00014 University of Helsinki, Finland
6 Department of Virology, Haartman Institute, PO Box 21, FIN-00014 University of Helsinki, Finland
7 HUCH Laboratory Diagnostics, PO Box 403, FIN-00029 HUS, Helsinki, Finland
Correspondence
Åke Lundkvist
Ake.Lundkvist{at}smi.ki.se
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Published online ahead of print on 28 April 2006 as DOI 10.1099/vir.0.81643-0.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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), Foot-and-mouth disease virus (Thomson et al., 2003), parvovirus (Barker & Parrish, 2001), as well as for infectious canine hepatitis virus (Woods, 2001) and avian influenza viruses (Stallknecht et al., 1990). However, only limited data are available concerning the potential of rodent-borne viruses, transmitted without an intermediate vector, to remain infectious outside their natural hosts.
Many rodent populations undergo strong density fluctuations. The temporal low host-population density is critical for long-term persistence of rodent-borne viruses. The capability of viruses to avoid extinction depends on the host-population dynamics and on the specific characteristics of the host–virus interaction. Recently, Sauvage et al. (2003) highlighted the importance of potential survival of Puumala hantavirus (PUUV) outside the rodent host for its persistence and transmission dynamics. Mathematical modelling suggested that an indirect mode of transmission via the natural environment and prolonged survival outside the host was required to generate an epidemic pattern compatible with the one observed (Sauvage et al., 2003). Prolonged contagiousness outside the host may facilitate the persistence of viruses during a temporal loss of the infection in the host population. Such persistence in the environment has also been speculated to play a role in the dynamics of Cowpox virus, another rodent-borne virus (Begon et al., 2003). Thus, the longevity in the environment might be a common adaptive characteristic of rodent-borne viruses, transmitted without intermediate vectors, in maintaining endemic infection dynamics.
Hantaviruses (family Bunyaviridae) are enveloped, three-segmented, negative-stranded RNA viruses. Hantaviruses have co-evolved with their rodent hosts through millions of years and each hantavirus has its own specific rodent host species (for a review, see Vapalahti et al., 2003). PUUV and its host, the bank vole (Brummer-Korvenkontio et al., 1980), are found in most of Europe. Tula virus (TULV) is carried by the European common vole (Microtus arvalis) (Plyusnin et al., 1994) and is distributed widely in central and eastern Europe. PUUV is the causative agent of nephropathia epidemica, a mild form of haemorrhagic fever with renal syndrome, with thousands of diagnosed cases in Europe annually, although TULV is believed to be non-pathogenic for humans (Vapalahti et al., 2003).
Hantavirus infections have not been reported to cause any apparent clinical illness in the carrier rodents (Bernshtein et al., 1999; Botten et al., 2002; Compton et al., 2004; Gavrilovskaya et al., 1990; Hutchinson et al., 1998; Lee et al., 1981). Hantavirus infection is chronic (for review, see Meyer & Schmaljohn, 2000) and the transmission is horizontal. Infectious PUUV is secreted in urine, faeces and saliva and the shedding starts approximately 1 week after infection (Gavrilovskaya et al., 1990). Although hantaviruses are transmitted via indirect and direct contacts (Bernshtein et al., 1999; Botten et al., 2002; Gavrilovskaya et al., 1990; Kariwa et al., 1998; Lee et al., 1981; Nuzum et al., 1988; Yanagihara et al., 1985), the relative importance of the different modes of transmission is not known. The resistance of hantaviruses against environmental conditions has been studied mainly in the context of inactivation procedures (Johnson, 1989; Schmaljohn et al., 1998). However, more information on the longevity of hantaviruses is needed for a better understanding of the epidemiological patterns, both in rodent and human populations.
Here, we have studied the survival of PUUV outside its host by exposing bank voles to beddings of infected donor bank voles (in vivo experiments). As the first results showed an unexpectedly long time-period of indirect transmission of PUUV between bank voles, we extended the in vivo experiments, and tested the survival of hantaviruses in cell culture. In these in vitro experiments, PUUV and TULV were exposed to different temperatures, either in cell culture medium or after drying.
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METHODS |
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). Throughout the experiment, no direct contact was allowed between individuals. The voles were held individually in polycarbonate rearing cages (28x17x12 cm) with wood shavings as bedding. The cages were in HEPA-filtered isolators, at room temperature (approx. 22 °C) and humidity between 40 and 60 %. The distance between cages was more than 15 cm, which is enough to prevent the intercage transmission of PUUV in the isolators (our unpublished observations). The photoperiod was constant: 16 h light and 8 h dark. Commercial mouse pellets and water were provided ad libitum. Fresh apples and lettuce were supplied once a week. For rearing conditions and handling of the animals, the guidelines and animal experimentation permits of the Swedish Institute for Infectious Disease Control (SMI) were followed.
The experiment was run in two trials. In the first trial, there were 15 donor individuals and five recipient groups (RGr) (15 recipients per group, altogether 75 recipient individuals). In the second trial, there were six donors and 60 recipient individuals divided into 10 RGr to prolong the study. The recipient individuals were divided randomly into RGr, taking, however, into account the gender and the age of available individuals. On day 0, the donor bank voles were inoculated subcutaneously with 100 bank vole ID50 of PUUV strain Kazan-wt-II (passaged twice in colonized bank voles). They were held individually in cages in isolators. On day 10, each donor was moved into a new separate clean experimental cage. On day 17, the donors were removed from the experimental cages and they were bled, sacrificed and sampled for tissues. Subsequently, also on day 17, the first RGr (RGr1) were moved individually into the experimental cages and exposed to the donors' beddings for 3 days (until day 20), when they were moved into clean management cages (individually) for 15 days to develop the infection. The second RGr (RGr2) individuals were put into the experimental cages for the next 3 days (from days 20 to 23). The procedure was continued in the same manner for all RGrs (in trial 1 until RGr5 and in trial 2 until RGr10). After 15 days in management cages, the animals were bled, sacrificed and dissected, tissues were sampled, weights measured and sexual maturation status checked (for females: open or closed vagina and uterus size; for males: testicle size).
Each of the experimental cages was occupied every day during the study, but no direct contact was allowed between any individual during the experiment, e.g. the fifth RGr individuals were in the experimental cages from days 12 to 15 and the individuals of RGr10 from days 27 to 30 following removal of the donor animals.
The 3 day period of exposure for the recipients was chosen based on the results found in the literature: shedding or transmission of hantaviruses in less than 5 days post-infection has not been reported. The earliest transmission of PUUV to other bank voles was reported by Gavrilovskaya et al. (1990) to occur 5 days after infection. The observed start of transmission and/or shedding of other hantaviruses depended on the study: e.g. Yanagihara et al. (1985) reported PUUV transmission 2 weeks after infection, Lee and his co-workers (1981) detected Hantaan virus in urine 7 days post-inoculation, Botten et al. (2002) found Sin Nombre virus RNA from saliva samples starting at day 15 post-infection, Kariwa et al. (1998) detected Seoul virus RNA on day 7 post-infection and Hutchinson and her collaborators (1998) reported Black Creek Canal virus in saliva 7 days post-infection. To confirm that the recipient individuals did not shed the virus while they were in the experimental cages, urine samples from the RGr1 individuals were collected when they were removed from the experimental cages. All these samples were negative for viral RNA by RT-PCR (see below). Therefore, the 3 day stay in the experimental cages was assumed to be short enough to prevent the shedding of the virus in any way by the recipient individuals.
Fourteen female and seven male bank voles were used as donors. The age of the donors at inoculation varied between 8 and 21 weeks (mean 15 weeks). The recipients were 7–24 weeks old (mean 15 weeks) when they were exposed to the secreted virus. Among the recipients, 57.5 % were females, 42.5 % males and 92 % were sexually mature.
Detection of PUUV infection.
PUUV infection was studied using a nested RT-PCR to detect PUUV S-segment RNA in lung and urine samples from bank voles, as described earlier (Plyusnin et al., 1997). RNA extraction from bank vole lung tissue and urine was carried out using the Ultraspec RNA isolation system (Biotech Laboratory) according to the manufacturer's instructions. Serum samples were screened for IgG antibodies using an IgG enzyme-immunoassay (EIA) as described earlier (Klingström et al., 2004).
Statistical analyses.
We used Pearson 
2 test, Fisher's exact test and Student's t-test in data analyses in SPSS for Windows.
In vitro experiments.
In the in vitro experiment, the longevity of PUUV and TULV was studied in cell culture supernatants at different temperatures. The incubations were done either in the cell culture medium (designated below as ‘wet’) or after drying on glass surfaces of microscope spot slides (designated below as ‘dry’) (Fig. 1). PUUV strain Sotkamo (Vapalahti et al., 1992) and TULV strain Moravia (Vapalahti et al., 1996), both adapted to Vero E6 cell culture, were used.
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), 10 µl of each virus dilution was applied on spots of two sterilized 10-spot-slides in duplicate. The virus suspension was subsequently air-dried for 15 min in a biosafety laminar hood at room temperature. In the wet experiment (Fig. 1), 100 µl of each dilution was put into 1.5 ml microtubes (one microtube per temperature per time period). Both the slides of dry-treated samples and the microtubes of wet-treated samples were stored in closed 50 ml tubes during the incubation. The samples were incubated at temperatures of –20, 4, 23, 37 and 56 °C for various time periods. After the incubation, 10 µl of each wet sample was applied to two sterilized slides (two wells per slide) as described above. Immediately afterwards, 30 µl cell suspension (containing approximately 48 000 Vero E6 cells) was applied to the wet samples. The same amount of cells was applied on the dried samples (two slides per temperature per time period) after the incubation. The slides were held in a humid incubation chamber at 37 °C (5 % CO2) during the infection. After 46±6 h, the slides were washed with PBS, air-dried and fixed with ice-cold acetone. Infected cells were detected by an immunofluorescence assay as described earlier (Vapalahti et al., 1995).
Slides were screened by fluorescence microscopy using a 400-fold magnification. Altogether 20 microscopic fields (in two wells on two slides) were observed randomly for each of the studied dilutions. Based on the initial titrations, optimal virus dilutions were selected for further studies; the PUUV samples were undiluted [producing 6.9x105 focus-forming units (f.f.u.) ml–1], the TULV samples from the incubation temperatures –20, 4, 23 and 37 °C were either undiluted or diluted 1/10 (producing 8.8x105 f.f.u. ml–1), and undiluted for the samples that were incubated at 56 °C. The proportion of cell coverage in each of the observed fields of vision was approximated and the number of virus-positive foci in the microscopic fields was counted. Only fields with more than 50 % of confluence were counted. For each field with <100 % cell coverage, the number of positive foci was recalculated to represent 100 % cell coverage. The results shown in Figs 2 and 3 represent a mean of 20 vision fields.
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RESULTS |
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). As no end point for the survival of PUUV outside the host was found in the first trial (isolators 1–3), a second, extended trial was performed (isolators 4–6). Altogether, there were 10 RGr in the second trial and none of the voles in RGr6–10 (days 15 to 30) was infected. PUUV remained infectious outside the host for up to 12–15 days. There was no difference in the proportion of infected individuals in the different RGr (Table 1).
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), and 90 % had seroconverted. Of the 135 recipients, 32 were positive as determined with RT-PCR (Table 1), and nine of them had seroconverted 17 days after the first contact with the donor beddings. All urine samples from the RGr1 animals were negative by RT-PCR at the end of the exposure (day 3). Donors 12, 15 and 17 infected individuals only from the fifth RGr, which were exposed to the donors' beddings from days 12 to 15, showing that the recipients were exposed to the virus shed by the donors, and not by virus shed by infected individuals in the previous RGr in the experimental cages.
Possible risk factors for infection of the recipients were further studied in the RGr1–5. Of these 105 individuals, 59 % were females and 41 % were males. Neither sex, nor maturation status of the recipients had a significant effect on the infection risk (gender: 2=0.28, d.f.=1, P=0.60, maturity: Fisher's exact test P=0.77). There was no difference in the weight or age between the infected and uninfected recipients (mean weight±SD, infected: 22.1±3.5 g (n=31), uninfected: 21.9±4.3 g (n=69), t=0.16, d.f.=98, P=0.87; mean age±SD in weeks, infected: 16.2±4.6 (n=32), uninfected: 14.9±5 (n=72), t=1.19, d.f.=102, P=0.28). The significance of the results did not differ when the recipients (n=35), which were exposed to donors that did not transmit the virus further (donors 7, 8, 10, 14, 19 and 21), were omitted from the analyses.
Altogether, 15 of 21 donors transmitted the virus to a recipient. Female donors infected the recipients more often than males (Fisher's exact test P=0.006). Of 14 female donors, 13 transmitted the virus further, whereas only two of seven male donors transmitted PUUV to recipients.
In vitro experiments
Cell-culture grown PUUV and TULV were exposed to different temperatures, either in cell culture medium or after drying, and the amount of infectious virus was quantified at different time points. The titre of the original input virus was 6.9x105 or 8.8x105 f.f.u. ml–1, producing approximately 35 or 45 foci per visual field for PUUV (undiluted) or TULV (1/10 dilutions), respectively (Fig. 2a and b). When the viruses were dried at room temperature before incubation (the same titres as in ‘wet’ treatment), they lost most of their infectivity (Fig. 2c and d). As expected, PUUV and TULV were stable when frozen at –20 °C. Furthermore, both viruses were still infectious after 18 days of incubation in cell culture medium at 4 °C (Fig. 2). At room temperature (23 °C) the viruses lost their capability to infect cells in 24 h when dried, but were still infectious after 5 days in a wet environment. At 37 °C, the viruses were completely inactivated within 24 h. Fifteen minutes at 56 °C was enough to inactivate viruses in cell culture medium. However, when the viruses were dried before incubation at 56 °C, a fraction of them remained infectious for 1 h (Fig. 3). Dried TULV was completely inactivated within 2 h at 56 °C.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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), Seoul (Kariwa et al., 1998) and Hantaan (Lee et al., 1981), we demonstrated that the indirect transmission occurs over an extended time-period. The results highlight the importance of PUUV survival outside the rodent host for transmission dynamics and human risk. Mathematical modelling by Sauvage et al. (2003) suggested that an indirect mode of transmission via a contaminated environment and prolonged virus survival outside the host was required to generate an epidemic pattern compatible with the observed one for PUUV (Sauvage et al., 2003). Interestingly, the authors used an estimation of 1 week for the survival of PUUV (Sauvage et al., 2003), which correlates well with our experimental results. The recipients in the present study were exposed to relatively freshly inoculated donors that had received a high inoculum, which may have resulted in an increased virus production during the early stages of infection. In a natural situation, persistently infected voles with a lowered virus production might be more numerously represented than those recently infected.
The role of indirect (aerosols) and direct (physical contacts) transmission modes in hantavirus dynamics, as well as the main route of the shedding of hantaviruses, have been discussed extensively and the results have been rather conflicting (e.g. Botten et al., 2002; Gavrilovskaya et al., 1990; Hinson et al., 2004; Hutchinson et al., 1998; Kariwa et al., 1998; Klein et al., 2000, 2001, 2004; Meyer & Schmaljohn, 2000; Padula et al., 2004; Vapalahti et al., 1999). For an efficient transmission via saliva, direct contacts are needed, since the amount of saliva secreted into the environment is likely to be very low. Transmission via saliva is often thought to be connected with aggressive behaviour and biting between rodents. In contrast, shedding of the virus in urine and faeces would enhance the probability of indirect transmission, since the amounts of secreted urine and faeces exceed that of saliva. Most likely both direct and indirect transmissions are involved in the infection dynamics of hantaviruses, but the importance of the different modes could vary depending on the hantavirus species, host-population dynamics, seasonal demographical features and related changes in behaviour of the host species, and on the environment. Different functional groups in rodent populations (breeding females and males, non-breeding subadults, juveniles) show very different levels of aggression and activity.
In addition, transmission strategies among the various hantaviruses may differ (Hutchinson et al., 1998). Different kinds of optimal persistence and transmission strategies may have evolved during the long co-evolution between hantaviruses and their rodent hosts (Vapalahti et al., 1999). The distribution ranges of PUUV and TULV cover mostly boreal and temperate regions where environmental conditions could be selective for prolonged survival.
We could not find any differences in the infection rates of recipient voles due to age, weight, sex or the maturation status. In field studies, characteristics like age, weight and breeding status of bank voles have been found to influence the PUUV seroprevalence (Bernshtein et al., 1999; Escutenaire et al., 2000, 2002; Niklasson et al., 1995; Olsson et al., 2002; Verhagen et al., 1986, 1987). Although the reports on gender-related differences have not been systematical, higher infection rates in old-breeding males have been observed in some studies (Bernshtein et al., 1999; Escutenaire et al., 2002; Olsson et al., 2002). On the other hand, we found that female donors infected more recipients than male donors. It remains to be seen if this is true in nature, in spite of the higher seroprevalence in breeding males.
Indirect transmission makes the transmission rate less dependent on the host density and enhances the persistence of virus in the host population (Sauvage et al., 2003); the northern Europe bank vole populations vary cyclically with deep decline phases (crashes), which last for more than a year (Hanski et al., 1994; Hansson & Henttonen, 1988). During crashes, the bank vole density may be extremely low, clearly less than one vole per hectare (Prévot-Julliard et al., 1999). The prolonged survival of PUUV is likely to enhance its transmission, especially during these low bank vole densities. Moreover, PUUV might persist in an area despite the temporary loss of infectious bank voles from the population (Sauvage et al., 2003) or even a temporary loss of the host individuals themselves.
Our results showed that the longevity of PUUV and TULV depends on the temperature and moisture. In nature, there are additional physical and chemical factors, like UV light, sunlight and pH, which may have an influence on the longevity of viruses. However, during the winter in northern Europe, voles spend most of their time under the snow cover in rather stable environmental conditions. A thick snow cover maintains a stable temperature and humidity, and protects secreted viruses from the UV light. Thus, we assume that the significance of the prolonged longevity of PUUV is more important during winter than during summer, and in northern Europe than in more southern and drier zones. In addition to the geographical differences in rodent dynamics and habitat fragmentation, environmental factors influencing the survival of PUUV may partly explain the regional differences in the human epidemiology of nephropathia epidemica in Europe. In northern Europe there are thousands of diagnosed cases annually, whereas in temperate, more populated Europe, the annual number of human cases is only some hundreds (Vapalahti et al., 2003).
The infectivity of viruses in cell culture medium was lost within 5–11 days at 23 °C, which is in line with the 12–15 days survival of PUUV observed in the animal experiments. The slightly longer survival of PUUV shed by bank voles compared with virus in cell culture might be attributable to a different pH or protein content, or due to a higher virus titre; the titre of PUUV excreted by our experimental animals is unknown. Additionally, since the infectivity of PUUV in bank vole decreases after passage in Vero E6 cell culture (Lundkvist et al., 1997), it is possible that other properties also change during cell culture adaptation.
The inactivation time of PUUV and TULV in cell culture depended on whether they were dried or not. Both viruses were inactivated within a 15 min incubation at 56 °C in cell culture medium that is compatible with the present recommendations for hantavirus heat inactivation, 30 min at 60 °C (Johnson, 1989). Based on the results presented in Schmaljohn et al. (1998), dried Hantaan virus remained viable for several days at room temperature. Our results indicated that drying the viruses decreased the infectivity considerably (Fig. 2), but a fraction still remained infectious and may be more resistant to heat. Thus, the increased stability of dried viruses should be taken into consideration when these viruses are inactivated.
The prolonged survival in the environment is a well known phenomenon in the epidemiology of some viral pathogens. However, this is the first time prolonged survival has been proven for hantaviruses. Prolonged survival of rodent-borne viruses outside the host is likely to increase the fitness of the virus and may therefore be selected for at natural dynamical conditions. Rodents represent the only evolutionary setting for hantaviruses: no arthropod vector is known – unlike for other members of the family Bunyaviridae – and human infections have no role in hantavirus epizootiology. Conceivably, the prolonged survival could well have been a significant fitness factor developed and selected for during the co-evolution of hantaviruses for millions of years together with their rodent hosts. It will be of interest to learn whether other rodent-borne viruses, such as arenaviruses, share this property and whether hantaviruses differ from the other arthropod-borne genera of the family Bunyaviridae.
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ACKNOWLEDGEMENTS |
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Received 27 October 2005;
accepted 15 April 2006.
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