Gert E. Olsson

Demographic factors associated with hantavirus infection in bank voles (Clethrionomys glareolus)

The bank vole (Clethrionomys glareolus) is the natural reservoir of Puumala virus (PUUV), a species in the genus Hantavirus. PUUV is the etiologic agent of nephropathia epidemica, a mild form of hemorrhagic fever with renal syndrome. Factors that influence hantavirus transmission within host populations are not well understood. We evaluated a number of factors influencing on the association of increased PUUV infection in bank voles captured in a region in northern Sweden endemic for the virus. Logistic regression showed four factors that together correctly predicted 80% of the model outcome: age, body mass index, population phase during sampling (increase, peak, or decline/low), and gender. This analysis highlights the importance of population demography in the successful circulation of hantavirus. The chance of infection was greatest during the peak of the population cycle, implying that the likelihood of exposure to hantavirus increases with increasing population density.

Puumala Hantavirus Excretion Kinetics in Bank Voles (Myodes glareolus)

One-sentence summary for table of contents: Virus may be transmitted by saliva, urine, and feces, and saliva may play a role in transmission to humans.

Human Hantavirus Infections, Sweden

The prevalent human hantavirus disease in Sweden is nephropathia epidemica, which is caused by Puumala virus and shed by infected bank voles (Clethrionomys glareolus). To evaluate temporal and spatial patterns of this disease, we studied 2,468 reported cases from a highly disease-endemic region in northern Sweden. We found that, in particular, middle-aged men living in rural dwellings near coastal areas were overrepresented. The case-patients were most often infected in late autumn, when engaged in activities near or within manmade rodent refuges. Of 862 case-patients confident about the site of virus exposure, 50% were concentrated within 5% of the study area. The incidence of nephropathia epidemica was significantly correlated with bank vole numbers within monitored rodent populations in part of the region. Understanding this relationship may help forestall future human hantavirus outbreaks.

Hantaviruses and their hosts in Europe: reservoirs here and there, but not everywhere?

Five hantaviruses are known to circulate among rodents in Europe, and at least two among insectivores. Four (Dobrava, Saaremaa, Seoul, and Puumala [PUUV] viruses) are clearly associated with hemorrhagic fever with renal syndrome (HFRS). PUUV, the most common etiological agent of HFRS in Europe, is carried by the bank vole (Myodes glareolus), one of the most widespread and abundant mammal species in Europe. This host-virus system is among hantaviruses also the most studied one in Europe. However, HFRS incidence varies throughout the continent. The spatial as well as temporal variation in the occurrence of HFRS is linked to geographic differences in the population dynamics of the reservoir rodents in different biomes of Europe. While rodent abundance may follow mast seeding events in many parts of temperate Europe, in northern (N) Europe multiannual cycles in population density exist as the result of the interaction between rodent populations and specialist predator populations in a delayed density-dependent manner. The spatial distribution of hantaviruses further depends on parameters such as forest patch size and connectivity of the most suitable rodent habitats, and the conditions for the survival of the virus outside the host, as well as historical distribution patterns (phylogeographies) of hosts and viruses. In multiannually fluctuating populations of rodents, with population increases of great amplitude, one should expect a simultaneous build-up of recently hantavirus-infected (shedding) rodents. The increasing number of infectious, virus-shedding rodents leads to a rapid transmission of hantavirus across the rodent population, and to humans. Our review discusses these aspects for PUUV, the only European hantavirus for which there is a reasonable, yet still far from complete, ecological continental-wide understanding. We discuss how this information could translate to other European hantavirus-host systems, and where the most important questions lie for further research.

Puumala Hantavirus Viremia Diagnosed by Real-Time Reverse Transcriptase PCR Using Samples from Patients with Hemorrhagic Fever and Renal Syndrome

ABSTRACT Puumala virus (PUUV) is the endemic hantavirus in northern Sweden and causes nephropathia epidemica (NE), a milder form of hemorrhagic fever with renal syndrome. There is a need for fast and reliable diagnostics to differentiate the disease from other infections. By aligning virus RNA sequences isolated from 11 different bank voles and one human patient, we designed a real-time reverse transcriptase (RT) PCR method for detection of PUUV RNA. The real-time RT-PCR assay showed linearity from 20 to 2 × 106 virus copies with a correlation coefficient above 0.98 to 0.99 for all experiments. The detection threshold for PUUV cDNA was two copies per reaction. A two-step qualitative RT-PCR to detect PUUV RNA showed 100% concordance with the real-time RT-PCR assay. PUUV RNA viremia was detected in 33 of 34 PUUV immunoglobulin M (IgM)-positive patients with typical clinical NE disease from the region of endemicity. One PUUV IgM-negative sample had PUUV RNA, and 4 days later, the patient was IgM positive. Of samples with indeterminate IgM, 43% were PUUV RNA positive. The kinetics of antibody titers and PUUV viremia were studied, and five of six NE patients displayed a decrease in PUUV viremia a few days after disease outbreak coupled with an increase in PUUV IgM and IgG. In one patient with continuously high PUUV RNA levels but low IgM and no IgG response, the infection was lethal. These findings demonstrated that real-time RT-PCR is a useful method for diagnosis of PUUV viremia and for detecting PUUV RNA at early time points, before the appearance of IgM antibodies.

Predicting High Risk for Human Hantavirus Infections, Sweden

An increased risk for hemorrhagic fever with renal syndrome caused by Puumala hantavirus was forecast for Sweden in 2007. The forecast was based on a predicted increase in the number of Myodes glareolus rodents (reservoir hosts). Despite raised awareness and preparedness, the number of human cases during July 2007–June 2008 was 1,483, a new high.

Tnf-α expression and promoter sequences reflect the balance of tolerance/resistance to Puumala hantavirus infection in European bank vole populations.

The tumor necrosis factor-alpha (TNF-α) influences the ability to limit parasite infection but its over-production might result in inflammatory disorders. The level of Tnf-α gene expression could thus mediate a balance of tolerance/resistance to infections. This study focused on Puumala hantavirus (PUUV) infection in its rodent host, the bank vole (Myodes glareolus). In humans, PUUV is responsible of a mild form of hemorrhagic fever with renal syndrome, nephropathia epidemica (NE). The severity of NE is associated with an over-production of TNF-α. By contrast, PUUV infection in bank vole is chronic and asymptomatic. It is likely that different coevolutionary histories between PUUV and its hosts could lead to different balances of resistance/tolerance to PUUV infection, at least partly mediated by variable production levels of TNF-α. We investigated the hypothesis that bank voles from PUUV endemic areas should exhibit higher levels of tolerance, i.e. lower levels of TNF-α production, than bank voles from areas where PUUV prevalence is low. For this purpose, we analysed variations of Tnf-α gene expression and promoter sequences among European populations of bank voles. Our results revealed an absence of up-regulation of Tnf-α gene expression in PUUV infected bank voles and significant differences in Tnf-α gene expression level with regard to PUUV endemicity. These results corroborated the hypothesis of different balances of tolerance/resistance to PUUV. Two single-nucleotide polymorphism genotypes within the Tnf-α promoter (-302 GG/GG and -296 A/A) were associated with higher Tnf-α gene expression and were more frequent in non-endemic areas. This study emphasized the potential influence of selection acting on TNF-α production and mediating a tolerance/resistance balance to PUUV in bank voles. Further investigations, including the role of phenotypic plasticity and parasite communities on Tnf-α expression levels, should provide important keys to understand the prevalence of PUUV over Europe.

Puumala hantavirus and Myodes glareolus in northern Europe: no evidence of co-divergence between genetic lineages of virus and host

The genus Hantavirus (family Bunyaviridae) includes negative-strand RNA viruses that are carried by persistently infected rodent and insectivore species. Puumala virus (PUUV), carried by bank voles (Myodes glareolus), is a pathogenic hantavirus that causes outbreaks of mild haemorrhagic fever with renal syndrome across Europe. In northern Europe, PUUV is represented by several genetic lineages that are maintained by distinct phylogroups of bank voles. The present study describes sequences of new PUUV strains recovered from northern and southern regions of Scandinavia and compares phylogenetic relationships between north-European PUUV strains and M. glareolus. This analysis revealed contradictions in phylogenetic clustering and remarkable differences in estimated divergence times between the lineages of PUUV and its host, suggesting that the established PUUV lineages did not co-diverge with the distinct phylogroups of M. glareolus that carry them at present.

HANTAVIRUS ANTIBODY OCCURRENCE IN BANK VOLES (CLETHRIONOMYS GLAREOLUS) DURING A VOLE POPULATION CYCLE

Puumala virus, genus Hantavirus, is the etiologic agent of nephropathia epidemica, a mild form of hemorrhagic fever with renal syndrome. The bank vole (Clethrionomys glareolus) is the natural reservoir species of this hantavirus. We initiated sampling of bank voles at sites of recently identified human nephropathia epidemica cases and paired control sites in the fall of 1995 in coastal areas of northern Sweden. Sites were trapped annually in spring and fall until 1999. Prevalence of antibody to Puumala virus was similar among local bank vole populations in the two types of sites over time. During peak years, however, the absolute number of bank voles was higher in case sites than control sites. Consequently, the likelihood of Puumala virus exposure was increased at case sites during population highs. This would imply that the risk of Puumala virus exposure to conspecifics and humans is habitat and site dependent with a temporal component.

Dynamics and Drivers of Hantavirus Prevalence in Rodent Populations

Human encroachment on wildlife habitats has contributed to the emergence of several zoonoses. Pathogenic hantaviruses are hosted by rodents and cause severe diseases in the Americas and Eurasia. We reviewed several factors that potentially drive prevalence (the proportion of infected rodents) in host populations. These include demography, behavior, host density, small mammal diversity, predation, and habitat and landscape characteristics. This review is the first to include a quantitative summary of the literature investigating hantavirus prevalence in rodents. Demographic structure and density were investigated the most and predation the least. Reported effects of demographic structure and small mammal diversity were consistent, whereby reproductive males were most likely to be infected and prevalence decreased with small mammal diversity. The influences of habitat and landscape properties are often complex and indirect. The relationship between density and prevalence merits more investigation. Most hantavirus hosts are habitat generalists and their control is challenging. Incorporating all potential factors and their interactions is essential to understanding and controlling infection in host populations.