Habitat factors associated with bank voles (Clethrionomys glareolus) and concomitant hantavirus in northern Sweden

Puumala virus (PUUV), genus hantavirus, causes nephropathia epidemica, a mild form of hemorrhagic fever with renal syndrome in humans. In this study, bank voles, the natural reservoir of PUUV, were captured at locations of previous human PUUV exposure and paired controls within a region of high incidence in northern Sweden. The aim of the study was to evaluate the influence of environmental factors on the abundance of bank voles and the occurrence of PUUV. The total number of voles and the number of PUUV-infected voles did not differ between locations of previous human PUUV exposure and paired controls. The number of bank voles expressing antibodies to PUUV infection increased linearly with total bank vole abundance implying density independent transmission. Using principal component and partial correlation analysis, we found that particular environmental characteristics associated with old-growth moist forests (i.e., those dominated by Alectoria spp., Picea abies, fallen wood, and Vaccinium myrtillus) were also associated with increased abundance of bank vole and hence the number of PUUV-infected bank voles, whereas there were no correlations with factors associated with dry environments (i.e., Pinus sylvestris and V. vitis-idea). This suggests that circulation and persistence of PUUV within bank vole populations was influenced by habitat factors. Future modeling of risk of exposure to hantavirus and transmission of PUUV within vole populations should include the influence of these factors.     

Population, environmental, and community effects on local bank vole (Myodes glareolus) Puumala virus infection in an area with low human incidence

In this study, the distribution of Puumala hantavirus (PUUV) infection in local bank vole Myodes glareolus populations in an area with low human PUUV infection (nephropathia epidemica [NE]) incidence in northern Belgium was monitored for 2 consecutive years. Bank voles were trapped in preferred habitat and tested for anti-PUUV IgG. Infection data were related to individual bank vole features, population demography, and environmental variables. Rare occurrence of PUUV infection was found and PUUV prevalence was low compared with data from the high NE incidence area in southern Belgium. Small-scale climatic differences seemed to play a role in PUUV occurrence, vegetation index and deciduous forest patch size both influenced PUUV prevalence and number of infected voles in a positive way. The data suggested a density threshold in vole populations below which PUUV infection does not occur. This threshold may vary between years, but the abundance of bank voles does not seem to affect the degree of PUUV seroprevalence further. We found indications for a dilution effect on PUUV prevalence, dependent on the relative proportion of nonhost wood mice Apodemus sylvaticus in a study site. In conclusion, we regard the combination of a dilution effect, a possible threshold density that depends on local conditions, and a higher fragmentation of suitable bank vole habitat in our study area as plausible explanations for the sparse occurrence of PUUV infection and low prevalence detected. Thus, beside human activity patterns, local environmental conditions and rodent community structure are also likely to play a role in determining PUUV infection risk for humans.     

Hantavirus Research in Finland: Highlights and Perspectives

Finland has the highest incidence of hantavirus infections globally, with a significant impact on public health. The large coverage of boreal forests and the cyclic dynamics of the dominant forest rodent species, the bank vole Myodes glareolus, explain most of this. We review the relationships between Puumala hantavirus (PUUV), its host rodent, and the hantavirus disease, nephropathia epidemica (NE), in Finland. We describe the history of NE and its diagnostic research in Finland, the seasonal and multiannual cyclic dynamics of PUUV in bank voles impacting human epidemiology, and we compare our northern epidemiological patterns with those in temperate Europe. The long survival of PUUV outside the host and the life-long shedding of PUUV by the bank voles are highlighted. In humans, the infection has unique features in pathobiology but rarely long-term consequences. NE is affected by specific host genetics and risk behavior (smoking), and certain biomarkers can predict the outcome. Unlike many other hantaviruses, PUUV causes a relatively mild disease and is rarely fatal. Reinfections do not exist. Antiviral therapy is complicated by the fact that when symptoms appear, the patient already has a generalized infection. Blocking vascular leakage measures counteracting pathobiology, offer a real therapeutic approach.     

Complete Genome and Phylogeny of Puumala Hantavirus Isolates Circulating in France

Puumala virus (PUUV) is the agent of nephropathia epidemica (NE), a mild form of hemorrhagic fever with renal syndrome (HFRS) in Europe. NE incidence presents a high spatial variation throughout France, while the geographical distribution of the wild reservoir of PUUV, the bank vole, is rather continuous. A missing piece of the puzzle is the current distribution and the genetic variation of PUUV in France, which has been overlooked until now and remains poorly understood. During a population survey, from 2008 to 2011, bank voles were trapped in eight different forests of France located in areas known to be endemic for NE or in area from where no NE case has been reported until now. Bank voles were tested for immunoglobulin (Ig)G ELISA serology and two seropositive animals for each of three different areas (Ardennes, Jura and Orleans) were then subjected to laboratory analyses in order to sequence the whole S, M and L segments of PUUV. Phylogenetic analyses revealed that French PUUV isolates globally belong to the central European (CE) lineage although isolates from Ardennes are clearly distinct from those in Jura and Orleans, suggesting a different evolutionary history and origin of PUUV introduction in France. Sequence analyses revealed specific amino acid signatures along the N protein, including in PUUV from the Orleans region from where NE in humans has never been reported. The relevance of these mutations in term of pathophysiology is discussed.     

Central Nervous System and Ocular Manifestations in Puumala Hantavirus Infection

Puumala hantavirus (PUUV), carried and spread by the bank vole (Myodes glareolus), causes a mild form of hemorrhagic fever with renal syndrome (HFRS) called nephropathia epidemica (NE). Acute high fever, acute kidney injury (AKI), thrombocytopenia, and hematuria are typical features of this syndrome. In addition, headache, blurred vision, insomnia, vertigo, and nausea are commonly associated with the disease. This review explores the mechanisms and presentations of ocular and central nervous system involvement in acute NE.     

Epidemiology of nephropathia epidemica in Sweden

A comprehensive study of nephropathia epidemica (NE), caused by Puumala virus, was conducted in Sweden. Human sera from residents of various regions of Sweden were examined for antibody to Puumala virus, and the incidence of NE was determined. Small mammals were captured at locations throughout Sweden and were examined for antibody to Puumala virus and for antigen. The human serosurvey found the highest prevalence rates and the highest incidence rates in northern Sweden. The bank vole was found to be the most-abundant rodent, as well as the species most frequently positive for antibody. Antibody-positive voles were restricted to the northern two-thirds of the country, an area corresponding to that where most human disease was noted. These results suggest that the bank vole is the principal host of Puumala virus in Sweden and clearly establish the region near 64 degrees N as highly endemic for NE in humans.     

Nephropathia epidemica in Norway: description of serological response in human disease and implication of rodent reservoirs

In search for the Norwegian nephropathia epidemica (NE) agent, lung sections from small rodents and sera from human patients have been tested by indirect fluorescent antibody technique (IFAT). A cytoplasmatic antigen reacting with patient sera and a Korean hemorrhagic fever (KHF) reference antiserum was found in the lungs of 6 bank voles (Clethrionomys glareolus) from 2 different locations. Antibodies reacting with vole lung antigen (NE agent) and KHF agent in A-549 cells were detected in sera from 35/57 patients clinically suspected of having NE. Specific IgM antibodies were usually detected in "early" obtained sera. Positive sera had considerably higher titers against NE than KHF agent. One serum had an IgG titer of 160 against NE, but no detectable KHF antibodies. One patient had an atypical disease. Two NE patients must have been infected north of the distribution area for Cl. glareolus, suggesting the existence of other reservoir animals.     

Identification of FactorsInfluencing the Puumala Virus Seroprevalence within Its Reservoir in aMontane Forest Environment

Puumala virus (PUUV) is a major cause of mild to moderate haemorrhagic fever with renal syndrome and is transmitted by the bank vole (Myodes glareolus). There has been a high cumulative incidence of recorded human cases in South-eastern Germany since 2004 when the region was first recognized as being endemic for PUUV. As the area is well known for outdoor recreation and the Bavarian Forest National Park (BFNP) is located in the region, the increasing numbers of recorded cases are of concern. To understand the population and environmental effects on the seroprevalence of PUUV in bank voles we trapped small mammals at 23 sites along an elevation gradient from 317 to 1420m above sea level. Generalized linear mixed effects models(GLMEM) were used to explore associations between the seroprevalence of PUUV in bank voles and climate and biotic factors. We found that the seroprevalence of PUUV was low (6%–7%) in 2008 and 2009, and reached 29% in 2010. PUUV seroprevalence was positively associated with the local species diversity and deadwood layer, and negatively associated with mean annual temperature, mean annual solar radiation, and herb layer. Based on these findings, an illustrative risk map for PUUV seroprevalence prediction in bank voles was created for an area of the national park. The map will help when planning infrastructure in the national park (e.g., huts, shelters, and trails).     

Serologic evidence of Puumala virus infection in wild moose in northern Sweden

Puumala (PUU) virus is the causative agent of nephropathia epidemica, the Scandinavian form of hemorrhagic fever with renal syndrome. The infection is acquired by airborne transmission of PUU virus from its rodent reservoir, the bank vole. Besides serologic data indicating that the virus may spread also to heterologous rodents, there is little information on the susceptibility of wild living animals to PUU virus. We studied the occurrence of antibodies to PUU virus in serum samples from 427 wild-living moose, of which 260 originated from the PUU virus-endemic northern and central parts of Sweden and 167 originated from the southern, nonendemic part of Sweden. Samples from 5 animals showed reactivity in an ELISA for recombinant PUU virus nucleocapsid protein, an immunofluorescent assay, and a neutralization test. These 5 animals all originated from the PUU virus-endemic northern part of Sweden. In conclusion, 5 of 260 moose from the endemic region showed convincing serologic evidence of past PUU virus infection. The seroprevalence was low, suggesting that the moose is subjected to endstage infection rather than being part of an enzootic transmission cycle.     

A case-control study after a hantavirus infection outbreak in the south of Belgium: who is at risk?

Puumala is the most common hantavirus serotype in Europe and is spread mainly by the red bank vole. Between 1 July 1992 and 31 January 1994, an outbreak of Puumala virus-induced nephropathia epidemica (NE) occurred in the Belgian Ardennes. Serologically confirmed cases (n = 41) were compared with two groups of asymptomatic seronegative controls. Risks identified included sighting of living rodents, exposure to rodent droppings, and trapping rodents during the 4 weeks preceding onset of symptoms. Activities during this 4-week period that presented the greatest risk were woodcutting, reopening of a nonaerated room, and strenuous physical effort. This is the first case-control study on risk factors for NE in Europe. In comparison with the American form of hantavirus pulmonary syndrome, which is spread by deer mice, professional activity appears to be a more important risk factor for acquisition of hantavirus in Europe.     

Serological evidence of viruses naturally associated with the montane water vole (Arvicola scherman) in eastern France

We surveyed 12 populations of the montane water vole (Arvicola scherman), previously known as the fossorial form of the water vole A. terrestris, in eastern France for antibodies (immunoglobulin G) to Puumala virus (PUUV), lymphocytic choriomeningitis virus (LCMV), and cowpox virus (CPXV). Antibodies to PUUV were found in 9 (5.5%) of 164 voles from 7 populations, antibodies to LCMV were found in 13 (26.0%) of 50 voles from 2 populations, and antibodies to CPXV were found in 66 (41.8%) of 158 voles from 7 populations. Antibody status to CPXV was statistically associated with the phase of the A. scherman population density cycle and the percentage of grassland areas surrounding the sampling sites.     

First Molecular Evidence for Puumala Hantavirus in Poland

Puumala virus (PUUV) causes mild to moderate cases of haemorrhagic fever with renal syndrome (HFRS), and is responsible for the majority of hantavirus infections of humans in Fennoscandia, Central and Western Europe. Although there are relatively many PUUV sequences available from different European countries, little is known about the presence of this virus in Poland. During population studies in 2009 a total of 45 bank voles were trapped at three sites in north-eastern Poland, namely islands on Dejguny and Dobskie Lakes and in a forest near Mikołajki. S and M segment-specific RT-PCR assays detected PUUV RNA in three animals from the Mikołajki site. The obtained partial S and M segment sequences demonstrated the highest similarity to the corresponding segments of a PUUV strain from Latvia. Analysis of chest cavity fluid samples by IgG ELISA using a yeast-expressed PUUV nucleocapsid protein resulted in the detection of two seropositive samples, both being also RT-PCR positive. Interestingly, at the trapping site in Mikołajki PUUV-positive bank voles belong to the Carpathian and Eastern genetic lineages within this species. In conclusion, we herein present the first molecular evidence for PUUV in the rodent reservoir from Poland.     

Systematic literature review of symptoms, signs and severity of serologically confirmed nephropathia epidemica in paediatric and adult patients

The clinical picture of nephropathia epidemica (NE), a rodent-mediated Puumala virus (PUUV) zoonosis, appears to be different in paediatric and adult patients, since severe complications are seen only in adults. To confirm this clinical impression, we made a systematic literature review to determine whether the severity of NE is similar in children and adults. We searched PubMed for articles dealing with the clinical symptoms, physical signs and outcomes of patients with NE, published in English or the Nordic languages during the y 1968-2008, and found 53 containing sufficient original data in serologically confirmed cases. Forty-one of these described individual cases, 11 a series of consecutive patients and 1 both. The total number of patients was 537, of which 80 were paediatric cases. The frequency of benign symptoms and transient physical signs was quite similar in adults and children. However severe complications were reported only in adult patients (n = 26), of whom 9 died. The literature review confirmed the clinical impression that NE is milder in children than in adults. Children with PUUV infection rarely, if ever, need any invasive therapy.     

Hemorrhagic fever with renal syndrome (nephropathia epidemica) in Norway: seroepidemiology 1981-1985

An indirect fluorescent antibody technique (IFAT) was applied to serologically confirm the clinical diagnosis in 507 nephropathia epidemica (NE) suspected patients. Hantaan virus (HV), the agent of Korean hemorrhagic fever, which is serologically related to the NE agent, was used as antigen. Both IgG and IgM reactions were detected. High levels of IgG antibodies to HV were common, even in the acute phase of illness. Over a 5-year period, a total of 35% of the NE suspected patients revealed antibodies to HV, but this varied considerably in the different years. In 2 endemic areas the serological confirmation of the NE diagnosis was 60%. 82% of the seropositive NE patients lived in 4 endemic areas. The bank vole (Clethrionomys glareolus) was common in all areas and predominant in 2. The wood mouse (Apodemus sylvaticus) was abundant in the other 2. In years with high bank vole population, the number of seropositive NE cases increased, with a peak in October/November. When the bank vole population was low, the relatively few seropositive NE cases occurred more regularly throughout the year. Subclinical infections were common. Antibodies to HV were detected in 74% male and 26% female NE patients, but the ratio varied between age groups.     

Genetic Diversity of Puumala orthohantavirus in Rodents and Human Patients in Austria, 2012–2019

Puumala orthohantavirus (PUUV) has a wide distribution throughout Europe. Distinctive temporal patterns of spillover into the human population are related to population dynamics of the reservoir host, the bank vole (Clethrionomys glareolus). As the rodent host is tied to specific habitats with small individual ranges, PUUV genetic diversity is also highly correlated with geographic distance. Using sequenced portions of viral S and M segments, we determined whether geographic clusters were supported. Human cases of PUUV infections are concentrated in southeastern Austria. We detected four distinct genotypes: two genotypes of the Alpe-Adria (ALAD) lineage typically associated with southeast Europe, and two sublineages of the Central Europe (CE) lineage. One cluster of CE genotypes represents a phylogenetically distinct sublineage compared to previously reported CE clades, and extends the boundary of the CE lineage further south than previously reported.     

Borrelia burgdorferi Sensu Lato in Siberian chipmunks (Tamias sibiricus) introduced in suburban forests in France

Numerous vertebrate reservoirs have been described for Borrelia burgdorferi sensu lato (sl), which includes the etiological agents of Lyme Borreliosis (LB). The Siberian chipmunk (Tamias sibiricus) is a rodent originating from Asia, where it is suspected to be a B. burgdorferi reservoir. It has been intentionally released into the wild in Europe since the 1970s, but has not yet been subject to any study regarding its association with the LB agent. In this paper we studied Siberian chipmunk infestation with the LB vector (Ixodes ricinus) and infection prevalence by LB spirochetes in a suburban introduced population. We compared these findings with known competent reservoir hosts, the bank vole (Myodes [clethrionomys] glareolus) and wood mouse (Apodemus sylvaticus). All Siberian chipmunks were infested with larvae and larval abundance was higher in this species (mean number of larvae [95% Confidence Interval]: 73.5 [46.0, 117.2]) than in the two other rodent species (bank voles: 4.4 [3.0, 6.3] and wood mice: 10.2 [4.9, 21.2]). Significant factors affecting abundance of larvae were host species and sampling season. Nymphs were most prevalent on chipmunks (86.2%, mean: 5.1 [3.3, 8.0]), one vole carried only two nymphs, and none of the mice had any nymphs. Nymph abundance in chipmunks was affected by sampling season and sex. Furthermore, the infection prevalence of B. burgdorferi sl in the Siberian chipmunk was the highest (33.3%) and predominantly of B. afzelii. The infection prevalence was 14.1% in bank voles, but no wood mouse was found to be infected. Our results suggest that the Siberian chipmunk may be an important reservoir host for LB.     

Muju Virus,Harbored by Myodes regulus in Korea,Might Represent a Genetic Variant of Puumala Virus,the Prototype Arvicolid Rodent-Borne Hantavirus

The genome of Muju virus (MUJV), identified originally in the royal vole (Myodes regulus) in Korea, was fully sequenced to ascertain its genetic and phylogenetic relationship with Puumala virus (PUUV), harbored by the bank vole (My. glareolus), and a PUUV-like virus, named Hokkaido virus (HOKV), in the grey red-backed vole (My. rufocanus) in Japan. Whole genome sequence analysis of the 6544-nucleotide large (L), 3652-nucleotide medium (M) and 1831-nucleotide small (S) segments of MUJV, as well as the amino acid sequences of their gene products, indicated that MUJV strains from different capture sites might represent genetic variants of PUUV, the prototype arvicolid rodent-borne hantavirus in Europe. Distinct geographic-specific clustering of MUJV was found in different provinces in Korea, and phylogenetic analyses revealed that MUJV and HOKV share a common ancestry with PUUV. A better understanding of the taxonomic classification and pathogenic potential of MUJV must await its isolation in cell culture.     

Hantavirus infection in bank voles in the natural reservoir. Part 1. Characteristics of an infection process in bank voles]

The specific features of hantavirus infection in naturally infected bank voles (Clethrionomys glareolus), the principal host of hantavirus of the serotype Puumala, were studied during long-term observation of individually marked animals in the active focus of hemorrhagic fever with renal syndrome (HFRS) in the south of Udmurtia. The infection time in the bank voles was defined by paired serum seroconversion tests. In the natural focus, hantavirus was shown to cause asymptomatic persistent infection in the bank voles with the body's peak accumulation of the virus and its environmental discharge within the first month of infection. In this period the animals present the greatest epidemic and epizootic hazards. Hantavirus infection has no negative impact on the viability of bank voles.