Clas Ahlm

Rapid expansion and long-term persistence of elevated NK cell numbers in humans infected with hantavirus

Acute hantavirus infection in humans triggers a rapid expansion and long-term persistence of NK cells.

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.

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.

Vaccination with virus-like particles protects mice from lethal infection of Rift Valley Fever Virus

Rift Valley Fever virus (RVFV) regularly accounts for severe and often lethal outbreaks among livestock and humans in Africa. Safe and effective veterinarian and human vaccines are highly needed. We present evidence that administration of RVF virus-like particles (VLPs) induces protective immunity in mice. In an accompanying paper, (Habjan, M., Penski, N., Wagner, V., Spiegel, M., Overby, A.K., Kochs, G., Huiskonen, J., Weber, F., 2009. Efficient production of Rift Valley fever virus-like particles: the antiviral protein MxA can inhibit primary transcription of Bunyaviruses. Virology 385, 400-408) we report the production of these VLPs in mammalian cells. After three subsequent immunizations with 1x10(6) VLPs/dose, high titers of virus-neutralizing antibodies were detected; 11 out of 12 mice were protected from challenge and only 1 out of 12 mice survived infection in the control groups. VLP vaccination efficiently suppressed replication of the challenge virus, whereas in the control animals high RNA levels and increasing antibody titers against the nucleocapsid protein indicated extensive viral replication. Our study demonstrates that the RVF VLPs are highly immunogenic and confer protection against RVFV infection in mice. In the test groups, the vaccinated mice did not exhibit any side effects, and the lack of anti-nucleocapsid protein antibodies serologically distinguished vaccinated animals from experimentally infected animals.

Time to revise the paradigm of hantavirus syndromes? Hantavirus pulmonary syndrome caused by European hantavirus

Hantaviruses have previously been recognised to cause two separate syndromes: hemorrhagic fever with renal syndrome in Eurasia, and hantavirus pulmonary syndrome (HPS) in the Americas. However, increasing evidence suggests that this dichotomy is no longer fruitful when recognising human hantavirus disease and understanding the pathogenesis. Herein are presented three cases of severe European Puumala hantavirus infection that meet the HPS case definition. The clinical and pathological findings were similar to those found in American hantavirus patients. Consequently, hantavirus infection should be considered as a cause of acute respiratory distress in all endemic areas worldwide.

Outbreak of Puumala Virus Infection, Sweden

An unexpected and large outbreak of Puumala virus infection in Sweden resulted in 313 nephropathia epidemica patients/100,000 persons in Västerbotten County during 2007. An increase in the rodent population, milder weather, and less snow cover probably contributed to the outbreak.

The 2007 rift valley Fever outbreak in Sudan

Rift Valley fever (RVF) is a neglected, emerging, mosquito-borne disease with severe negative impact on human and animal health and economy. RVF is caused by RVF virus (RVFV) affecting humans and a wide range of animals. The virus is transmitted through bites from mosquitoes and exposure to viremic blood, body fluids, or tissues of infected animals. During 2007 a large RVF outbreak occurred in Sudan with a total of 747 confirmed human cases including 230 deaths (case fatality 30.8%); although it has been estimated 75,000 were infected. It was most severe in White Nile, El Gezira, and Sennar states near to the White Nile and the Blue Nile Rivers. Notably, RVF was not demonstrated in livestock until after the human cases appeared and unfortunately, there are no records or reports of the number of affected animals or deaths. Ideally, animals should serve as sentinels to prevent loss of human life, but the situation here was reversed. Animal contact seemed to be the most dominant risk factor followed by animal products and mosquito bites. The Sudan outbreak followed an unusually heavy rainfall in the country with severe flooding and previous studies on RVF in Sudan suggest that RVFV is endemic in parts of Sudan. An RVF outbreak results in human disease, but also large economic loss with an impact beyond the immediate influence on the directly affected agricultural producers. The outbreak emphasizes the need for collaboration between veterinary and health authorities, entomologists, environmental specialists, and biologists, as the best strategy towards the prevention and control of RVF.

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.

Prevalence of serum IgG antibodies to Puumala virus (haemorrhagic fever with renal syndrome) in northern Sweden.

A stratified and randomly-selected population sample was identified in 1990 in order to study the seroprevalence of nephropathia epidemica (haemorrhagic fever with renal syndrome) in Northern Sweden. Sera from 1538 subjects (750 men, 788 women), 25-64 years of age, were analysed for the presence of Puumala virus (PUV) specific-IgG by the indirect immunofluorescence antibody test. Specific IgG was detected in sera from 83 subjects (5.4%). Men and women had similar seroprevalence rates. The highest seroprevalences were found in subjects 55 years or older (8.0%) and among farmers and forestry workers (15.9%). The geographic distribution of seropositive individuals was uneven and there were significantly more seropositive persons in rural than in urban areas (P < 0.05).

Loss of Cell Membrane Integrity in Puumala Hantavirus-Infected Patients Correlates with Levels of Epithelial Cell Apoptosis and Perforin

ABSTRACT Hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome are two diseases caused by hantaviruses. Capillary leakage is a hallmark of hantavirus infection. Pathogenic hantaviruses are not cytotoxic, but elevated levels of serum lactate dehydrogenase (LDH), indicative of cellular damage, are observed in patients. We report increased levels of serum perforin, granzyme B, and the epithelial cell apoptosis marker caspase-cleaved cytokeratin-18 during Puumala hantavirus infection. Significant correlation was observed between the levels of LDH and perforin and the levels of LDH and caspase-cleaved cytokeratin-18, suggesting that tissue damage is due to an immune reaction and that epithelial apoptosis contributed significantly to the damage.