ABO and Rhesus Blood Groups in Acute Puumala Hantavirus Infection.

Puumala hantavirus (PUUV) causes hemorrhagic fever with renal syndrome. We aimed to evaluate whether ABO and rhesus blood groups associate with the susceptibility or the severity of PUUV infection. We analyzed blood groups in 289 adult patients treated in Tampere University hospital due to PUUV infection during the years 1982-2017. Patients' blood group distribution was compared to that of healthy, voluntary blood donors living in the Tampere University Hospital responsibility area (n = 21,833). The severity of PUUV infection, as judged by the severity of acute kidney injury (AKI), thrombocytopenia, inflammation, capillary leakage, and the length of hospital care, was analyzed across the groups. The ABO and rhesus blood group distributions did not differ between the patients and blood donors. Patients with non-O blood groups had lower systolic blood pressure compared to patients with blood group O, but there was no difference in other markers of capillary leakage or in the severity of AKI. Minor deviations in the number of platelets and leukocytes were detected between the O and non-O blood groups. To conclude, patients with blood group O may be less susceptible to hypotension, but otherwise blood groups have no major influences on disease susceptibility or severity during acute PUUV infection.

Hormonal Defects Are Common during Puumala Hantavirus Infection and Associate with Disease Severity and Biomarkers of Altered Haemostasis.

Central and peripheral hormone deficiencies have been documented during and after acute hantavirus infection. Thrombocytopenia and coagulation abnormalities are common findings in haemorrhagic fever with renal syndrome (HFRS). The associations between coagulation and hormonal abnormalities in HFRS have not been studied yet. Forty-two patients diagnosed with Puumala virus (PUUV) infection were examined during the acute phase and on a follow-up visit approximately one month later. Hormonal defects were common during acute PUUV infection. Overt (clinical) hypogonadism was identified in 80% of the men and approximately 20% of the patients had overt hypothyroidism. At the one-month follow-up visit, six patients had central hormone deficits. Acute peripheral hormone deficits associated with a more severe acute kidney injury (AKI), longer hospital stay and more severe thrombocytopenia. Half of the patients with bleeding symptoms had also peripheral hormonal deficiencies. Patients with free thyroxine levels below the reference range had higher D-dimer level than patients with normal thyroid function, but no thromboembolic events occurred. Acute phase hormonal abnormalities associate with severe disease and altered haemostasis in PUUV infection.

Inhibition of interferon I induction by non-structural protein NSs of Puumala virus and other vole-associated orthohantaviruses: phenotypic plasticity of the protein and potential functional domains.

The orthohantavirus Puumala virus (PUUV), which is transmitted by bank voles (Clethrionomys glareolus), and other vole-borne hantaviruses contain in their small (S) genome segment two overlapping open reading frames, coding for the nucleocapsid protein and the non-structural protein NSs, a putative type I interferon (IFN-I) antagonist. To investigate the role of NSs of PUUV and other orthohantaviruses, the expression pattern of recombinant NSs constructs and their ability to inhibit human IFN-I promoter activity were investigated. The NSs proteins of PUUV and related cricetid-borne orthohantaviruses showed strong inhibition of IFN-I promoter induction. We identified protein products originating from three and two methionine initiation codons in the NSs ORF of PUUV during transfection and infection, respectively. The three putative start codons are conserved in all PUUV strains analysed. Translation initiation at these start codons influenced the inhibitory activity of the NSs products, with the wild-type (wt) construct expressing two proteins starting at the first and second methionine and showing strong inhibition activity. Analysis of in vitro-generated variants and naturally occurring PUUV NSs proteins indicated that amino acid variation in the NSs protein is well tolerated, suggesting its phenotypic plasticity. The N-terminal 20-amino-acid region of the NSs protein was found to be associated with strong inhibition and to be highly vulnerable to amino acid exchanges and tag fusions. Infection studies using human, bank vole, and Vero E6 cells did not show obvious differences in the replication capacity of PUUV Sotkamo wt and a strain with a truncated NSs protein (NSs21Stop), showing that the lack of a full-length NSs might be compensated by its N-terminal peptide, as seen in transfection experiments. These results contribute to our understanding of virus-host interactions and highlight the importance of future innate immunity studies in reservoir hosts.

Rodent-Borne Orthohantaviruses in Vietnam, Madagascar and Japan.

Hantaviruses are harbored by multiple small mammal species in Asia, Europe, Africa, and the Americas. To ascertain the geographic distribution and virus-host relationships of rodent-borne hantaviruses in Japan, Vietnam, Myanmar, and Madagascar, RNAlater™-preserved lung tissues of 981 rodents representing 40 species, collected in 2011-2017, were analyzed for hantavirus RNA by RT-PCR. Our data showed Hantaan orthohantavirus Da Bie Shan strain in the Chinese white-bellied rat (Niviventer confucianus) in Vietnam, Thailand; orthohantavirus Anjo strain in the black rat (Rattus rattus) in Madagascar; and Puumala orthohantavirus Hokkaido strain in the grey-sided vole (Myodes rufocanus) in Japan. The Hokkaido strain of Puumala virus was also detected in the large Japanese field mouse (Apodemus speciosus) and small Japanese field mouse (Apodemus argenteus), with evidence of host-switching as determined by co-phylogeny mapping.

Coagulopathy in Acute Puumala Hantavirus Infection.

Puumala hantavirus (PUUV) causes a hemorrhagic fever with renal syndrome (HFRS), also called nephropathia epidemica (NE), which is mainly endemic in Europe and Russia. The clinical features include a low platelet count, altered coagulation, endothelial activation, and acute kidney injury (AKI). Multiple connections between coagulation pathways and inflammatory mediators, as well as complement and kallikrein-kinin systems, have been reported. The bleeding symptoms are usually mild. PUUV-infected patients also have an increased risk for disseminated intravascular coagulation (DIC) and thrombosis.

The Clinical Presentation of Puumala Hantavirus Induced Hemorrhagic Fever with Renal Syndrome Is Related to Plasma Glucose Concentration.

Puumala hantavirus (PUUV) causes a hemorrhagic fever with renal syndrome characterized by thrombocytopenia, increased capillary leakage, and acute kidney injury (AKI). As glucosuria at hospital admission predicts the severity of PUUV infection, we explored how plasma glucose concentration associates with disease severity. Plasma glucose values were measured during hospital care in 185 patients with PUUV infection. They were divided into two groups according to maximum plasma glucose concentration: P-Gluc < 7.8 mmol/L (n = 134) and P-Gluc ≥ 7.8 mmol/L (n = 51). The determinants of disease severity were analyzed across groups. Patients with P-Gluc ≥7.8 mmol/L had higher hematocrit (0.46 vs. 0.43; p < 0.001) and lower plasma albumin concentration (24 vs. 29 g/L; p < 0.001) than patients with P-Gluc < 7.8 mmol/L. They presented with higher prevalence of pulmonary infiltrations and pleural effusion in chest radiograph, higher prevalence of shock and greater weight change during hospitalization. Patients with P-Gluc ≥ 7.8 mmol/L were characterized by lower platelet count (50 vs. 66 × 109/L; p = 0.001), more severe AKI (plasma creatinine 272 vs. 151 µmol/L; p = 0.001), and longer hospital treatment (8 vs. 6 days; p < 0.001) than patients with P-Gluc < 7.8 mmol/L. Plasma glucose level is associated with the severity of capillary leakage, thrombocytopenia, inflammation, and AKI in patients with acute PUUV infection.

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.

MAIT cell activation is associated with disease severity markers in acute hantavirus infection.

Hantaviruses are zoonotic RNA viruses that cause severe acute disease in humans. Infected individuals have strong inflammatory responses that likely cause immunopathology. Here, we studied the response of mucosal-associated invariant T (MAIT) cells in peripheral blood of individuals with hemorrhagic fever with renal syndrome (HFRS) caused by Puumala orthohantavirus, a hantavirus endemic in Europe. We show that MAIT cell levels decrease in the blood during HFRS and that residual MAIT cells are highly activated. This activation correlates with HFRS severity markers. In vitro activation of MAIT cells by hantavirus-exposed antigen-presenting cells is dependent on type I interferons (IFNs) and independent of interleukin-18 (IL-18). These findings highlight the role of type I IFNs in virus-driven MAIT cell activation and suggest a potential role of MAIT cells in the disease pathogenesis of viral infections.

Circulating Extracellular Vesicle Tissue Factor Activity During Orthohantavirus Infection Is Associated With Intravascular Coagulation.

BACKGROUND: Puumala orthohantavirus (PUUV) causes hemorrhagic fever with renal syndrome (HFRS). Patients with HFRS have an activated coagulation system with increased risk of disseminated intravascular coagulation (DIC) and venous thromboembolism (VTE). The aim of the study was to determine whether circulating extracellular vesicle tissue factor (EVTF) activity levels associates with DIC and VTE (grouped as intravascular coagulation) in HFRS patients. METHODS: Longitudinal samples were collected from 88 HFRS patients. Patients were stratified into groups of those with intravascular coagulation (n = 27) and those who did not (n = 61). We measured levels of circulating EVTF activity, fibrinogen, activated partial prothrombin time, D-dimer, tissue plasminogen activator (tPA), plasminogen activator inhibitor 1 (PAI-1), and platelets. RESULTS: Plasma EVTF activity was transiently increased during HFRS. Levels of EVTF activity were significantly associated with plasma tPA and PAI-1, suggesting that endothelial cells could be a potential source. Patients with intravascular coagulation had significantly higher peak EVTF activity levels compared with those who did not, even after adjustment for sex and age. The peak EVTF activity value predicting intravascular coagulation was 0.51 ng/L with 63% sensitivity and 61% specificity with area under the curve = 0.63 (95% confidence interval, 0.51-0.76) and P = .046. CONCLUSIONS: Plasma EVTF activity during HFRS is associated with intravascular coagulation.

Puumala and Tula Virus Differ in Replication Kinetics and Innate Immune Stimulation in Human Endothelial Cells and Macrophages.

Old world hantaviruses cause hemorrhagic fever with renal syndrome (HFRS) upon zoonotic transmission to humans. In Europe, the Puumala virus (PUUV) is the main causative agent of HFRS. Tula virus (TULV) is also widely distributed in Europe, but there is little knowledge about the pathogenicity of TULV for humans, as reported cases are rare. We studied the replication of TULV in different cell types in comparison to the pathogenic PUUV and analyzed differences in stimulation of innate immunity. While both viruses replicated to a similar extent in interferon (IFN)-deficient Vero E6 cells, TULV replication in human lung epithelial (A549) cells was slower and less efficient when compared to PUUV. In contrast to PUUV, no replication of TULV could be detected in human microvascular endothelial cells and in macrophages. While a strong innate immune response towards PUUV infection was evident at 48 h post infection, TULV infection triggered only a weak IFN response late after infection of A549 cells. Using appropriate in vitro cell culture models for the orthohantavirus infection, we could demonstrate major differences in host cell tropism, replication kinetics, and innate immune induction between pathogenic PUUV and the presumably non- or low-pathogenic TULV that are not observed in Vero E6 cells and may contribute to differences in virulence.

Glycoprotein YKL-40 Is Elevated and Predicts Disease Severity in Puumala Hantavirus Infection.

Most cases of hemorrhagic fever with renal syndrome (HFRS) in Europe are caused by the Puumala hantavirus (PUUV). Typical features of the disease are increased vascular permeability, acute kidney injury (AKI), and thrombocytopenia. YKL-40 is an inflammatory glycoprotein involved in various forms of acute and chronic inflammation. In the present study, we examined plasma YKL-40 levels and the associations of YKL-40 with disease severity in acute PUUV infection. A total of 79 patients treated in Tampere University Hospital during 2005-2014 were studied. Plasma YKL-40 was measured in the acute phase, the recovery phase, and one year after hospitalization. Plasma YKL-40 levels were higher during the acute phase compared to the recovery phase and one year after hospitalization (median YKL-40 142 ng/mL, range 11-3320, vs. 45 ng/mL, range 15-529, vs. 32 ng/mL, range 3-213, p < 0.001). YKL-40 level was correlated with the length of hospital stay (r = 0.229, p = 0.042), the levels of inflammatory markers-that is, blood leukocytes (r = 0.234, p = 0.040), plasma C-reactive protein (r = 0.332, p = 0.003), and interleukin-6 (r = 0.544, p < 0.001), and maximum plasma creatinine level (r = 0.370, p = 0.001). In conclusion, plasma YKL-40 levels were found to be elevated during acute PUUV infection and correlated with the overall severity of the disease, as well as with the degree of inflammation and the severity of AKI.

Hypopituitarism after Orthohantavirus Infection: What is Currently Known?

Several case reports have described hypopituitarism following orthohantavirus infection, mostly following Puumala virus. The pathogenesis of this seemingly rare complication of orthohantavirus infection remains unknown. This review explores the possible pathophysiological mechanisms of pituitary damage due to orthohantavirus infection. In only three out of the 28 reported cases, hypopituitarism was detected during active infection. In the remaining cases, detection of pituitary damage was delayed, varying from two months up to thirteen months post-infection. In these cases, hypopituitarism remained undetected during the acute phase of infection or only occurred weeks to months post infection. Both ischemic and hemorrhagic damage of the pituitary gland have been detected in radiographic imaging and post-mortem studies in the studied case reports series. Ischemic damage could be caused by hypotension and/or vasospasms during the acute phase of hemorrhagic fever with renal syndrome (HFRS) while hemorrhage could be caused by thrombocytopenia, thrombopathy, and other known causes of coagulation disorders during orthohantavirus infection. Also, hypophysitis due to the presence of auto-antibodies have been suggested in the literature. In conclusion, a significant number of case reports and series describe hypopituitarism after orthohantavirus infection. In most cases hypopituitarism was diagnosed with a delay and therefore could very well be underreported. Clinicians should be aware of this potential endocrine complication, with substantial morbidity, and if unrecognized, significant mortality.

High plasma resistin associates with severe acute kidney injury in Puumala hantavirus infection.

BACKGROUND: Puumala hantavirus (PUUV) infected patients typically suffer from acute kidney injury (AKI). Adipokines have inflammation modulating functions in acute diseases including AKI. We examined plasma levels of three adipokines (resistin, leptin, and adiponectin) in acute PUUV infection and their associations with disease severity. METHODS: This study included 79 patients hospitalized due to acute PUUV infection. Plasma resistin, leptin, adiponectin, as well as IL-6 and CRP, were measured at the acute phase, recovery phase and one year after hospitalization. RESULTS: Plasma resistin levels were significantly higher in the acute phase compared to the recovery phase and one year after (median resistin 28 pg/mL (11-107) vs. 17 pg/mL (7-36) vs. 14 pg/mL (7-31), p<0.001). Maximum resistin concentration correlated with maximum plasma creatinine levels (r = 0.63; p<0.001). The higher the amount of albuminuria in the urine dipstick test (0-1+, 2+ or 3+) at admission, the higher the median of maximum resistin (24.7 pg/mL, 25.4 pg/mL and 39.6 pg/mL, respectively, p = 0.002). High resistin was also an independent risk factor for severe AKI (creatinine ≥353.6µmol/L) (OR 1.08, 95% CI 1.02-1.14). Neither plasma leptin nor adiponectin level had any correlation with creatinine concentration or the amount of albuminuria. CONCLUSIONS: Plasma resistin independently associates with the severity of AKI in acute PUUV infection. The association of resistin with the amount of albuminuria suggests that the level of plasma resistin is not only influenced by renal clearance but could have some role in the pathogenesis of AKI during PUUV infection.

Diminished coagulation capacity assessed by calibrated automated thrombography during acute Puumala hantavirus infection.

: Coagulation abnormalities are associated with Puumala-virus-induced hemorrhagic fever with renal syndrome (PUUV-HFRS). We evaluated the coagulation capacity of plasma during acute PUUV-HFRS by measuring thrombin generation using calibrated automated thrombography (CAT). The study cohort comprised 27 prospectively collected, consecutive, hospital-treated patients with acute PUUV infection. Blood samples were drawn in the acute phase and at the control visit approximately 5 weeks later. To evaluate thrombin generation, the lag time of initiation, endogenous thrombin potential (ETP), and peak and time to peak thrombin concentration were assessed by CAT in platelet poor plasma without corn trypsin inhibitor. Plasma levels of D-dimer, fibrinogen and prothrombin fragments (F1 + 2) were also evaluated. When the acute phase was compared with the control phase, ETP was decreased (median 1154 nmol/l/min, range 67-1785 vs. median 1385 nmol/l/min, range 670-1970; P < 0.001), while the lag time was prolonged (median 3.8 min, range 2.1-7.7 vs. median 2.9 min, range 2.0-4.1; P < 0.001). Low ETP correlated with low peak thrombin concentration (r = 0.833, P < 0.001). Prolonged time to peak associated with the lag time (r = 0.78, P < 0.001). ETP was associated with thrombocytopenia (r = 0.472, P = 0.015) and weakly with fibrinogen level (r = 0.386, P = 0.047). The measured CAT parameters did not associate with D-dimer and F1 + 2 levels. Decreased ETP together with low peak and prolonged lag time indicate decreased plasma potential for thrombin generation in vitro. Together with low platelet count and enhanced fibrinolysis, this further refers to altered blood coagulation and increased propensity toward bleeding in acute PUUV-HFRS.

Spatial prediction and validation of zoonotic hazard through micro-habitat properties: where does Puumala hantavirus hole - up?

BACKGROUND: To predict the risk of infectious diseases originating in wildlife, it is important to identify habitats that allow the co-occurrence of pathogens and their hosts. Puumala hantavirus (PUUV) is a directly-transmitted RNA virus that causes hemorrhagic fever in humans, and is carried and transmitted by the bank vole (Myodes glareolus). In northern Sweden, bank voles undergo 3-4 year population cycles, during which their spatial distribution varies greatly. METHODS: We used boosted regression trees; a technique inspired by machine learning, on a 10 - year time-series (fall 2003-2013) to develop a spatial predictive model assessing seasonal PUUV hazard using micro-habitat variables in a landscape heavily modified by forestry. We validated the models in an independent study area approx. 200 km away by predicting seasonal presence of infected bank voles in a five-year-period (2007-2010 and 2015). RESULTS: The distribution of PUUV-infected voles varied seasonally and inter-annually. In spring, micro-habitat variables related to cover and food availability in forests predicted both bank vole and infected bank vole presence. In fall, the presence of PUUV-infected voles was generally restricted to spruce forests where cover was abundant, despite the broad landscape distribution of bank voles in general. We hypothesize that the discrepancy in distribution between infected and uninfected hosts in fall, was related to higher survival of PUUV and/or PUUV-infected voles in the environment, especially where cover is plentiful. CONCLUSIONS: Moist and mesic old spruce forests, with abundant cover such as large holes and bilberry shrubs, also providing food, were most likely to harbor infected bank voles. The models developed using long-term and spatially extensive data can be extrapolated to other areas in northern Fennoscandia. To predict the hazard of directly transmitted zoonoses in areas with unknown risk status, models based on micro-habitat variables and developed through machine learning techniques in well-studied systems, could be used.

Experimental infections of wild bank voles (Myodes glareolus) from nephropatia epidemica endemic and non-endemic regions revealed slight differences in Puumala virological course and immunological responses.

In Europe, the occurrence of nephropathia epidemica (NE), a human disease caused by Puumala virus (PUUV), exhibits considerable geographical heterogeneity despite the continuous distribution of its reservoir, the bank vole Myodes glareolus. To better understand the causes of this heterogeneity, wild voles sampled in two adjacent NE endemic and non-endemic regions of France were infected experimentally with PUUV. The responses of bank voles to PUUV infection, based on the levels of anti-PUUV IgG and viral RNA, were compared. Slight regional differences were highlighted despite the high inter-individual variability. Voles from the NE non-endemic region showed greater immune responsiveness to PUUV infection, but lower levels of RNA in their organs than voles from the endemic region. These results suggest the existence of regional variations in the sensitivity of bank voles that could contribute to the apparent absence of PUUV circulation among voles and the absence of NE in the non-endemic region.

Glomerular Proteinuria Predicts the Severity of Acute Kidney Injury in Puumala Hantavirus-Induced Tubulointerstitial Nephritis.

BACKGROUND: Puumala virus (PUUV)-induced hemorrhagic fever with renal syndrome is common in many European countries. The typical renal histologic lesion is acute tubulointerstitial nephritis. We examined the type and kinetics of urine protein excretion and prognostic significance of proteinuria for the severity of acute kidney injury (AKI) in acute PUUV infection. METHODS: The amount of dipstick albuminuria at hospital admission was analyzed in 205 patients with acute PUUV infection. Dipstick albuminuria at admission was graded into 3 categories: 0-1+, 2+, and 3+. In 70 patients, 24-h urinary excretion of protein, overnight urinary excretion of albumin, immunoglobulin (Ig) G, and α1-microglobulin also were measured over 3 consecutive days during the hospital stay. RESULTS: Maximum median daily proteinuria, overnight albuminuria, and IgG excretion were observed over 5 days, while that of creatinine values was observed 9 days after the onset of the disease. The medians of maximum plasma creatinine levels during hospital stay were different in the 3 categories of dipstick albuminuria: 0-1+: 98 µmol/L (58-1,499), 2+: 139 µmol/L (71-829), and 3+: 363 µmol/L (51-1,285; p < 0.001). Dipstick albuminuria ≥2+ at admission could be detected in 89% of the patients who subsequently developed severe AKI. Glomerular proteinuria, but not tubular proteinuria (α1-microglobulin), correlated with the severity of the emerging AKI. CONCLUSION: In acute PUUV infection, maximum median proteinuria values preceded the most severe phase of AKI by a few days. A highly useful finding for clinical work was that a quick and simple albuminuria dipstick test at hospital admission predicted the severity of the upcoming AKI.

Host-Associated Absence of Human Puumala Virus Infections in Northern and Eastern Germany.

Human hantavirus disease cases, caused by Puumala virus (PUUV), are mainly recorded in western and southern areas of Germany. This bank vole reservoir survey confirmed PUUV presence in these regions but its absence in northern and eastern regions. PUUV occurrence is associated with the presence of the Western bank vole phylogroup.

Microevolution of bank voles (Myodes glareolus) at neutral and immune-related genes during multiannual dynamic cycles: Consequences for Puumala hantavirus epidemiology.

Understanding how host dynamics, including variations of population size and dispersal, may affect the epidemiology of infectious diseases through ecological and evolutionary processes is an active research area. Here we focus on a bank vole (Myodes glareolus) metapopulation surveyed in Finland between 2005 and 2009. Bank vole is the reservoir of Puumala hantavirus (PUUV), the agent of nephropathia epidemica (NE, a mild form of hemorrhagic fever with renal symptom) in humans. M. glareolus populations experience multiannual density fluctuations that may influence the level of genetic diversity maintained in bank voles, PUUV prevalence and NE occurrence. We examine bank vole metapopulation genetics at presumably neutral markers and immune-related genes involved in susceptibility to PUUV (Tnf-promoter, Tlr4, Tlr7 and Mx2 gene) to investigate the links between population dynamics, microevolutionary processes and PUUV epidemiology. We show that genetic drift slightly and transiently affects neutral and adaptive genetic variability within the metapopulation. Gene flow seems to counterbalance its effects during the multiannual density fluctuations. The low abundance phase may therefore be too short to impact genetic variation in the host, and consequently viral genetic diversity. Environmental heterogeneity does not seem to affect vole gene flow, which might explain the absence of spatial structure previously detected in PUUV in this area. Besides, our results suggest the role of vole dispersal on PUUV circulation through sex-specific and density-dependent movements. We find little evidence of selection acting on immune-related genes within this metapopulation. Footprint of positive selection is detected at Tlr-4 gene in 2008 only. We observe marginally significant associations between Mx2 genotype and PUUV genogroups. These results show that neutral processes seem to be the main factors affecting the evolution of these immune-related genes at a contemporary scale, although the relative effects of neutral and adaptive forces could vary temporally with density fluctuations. Immune related gene polymorphism may in turn partly influence PUUV epidemiology in this metapopulation.

Interferons Induce STAT1-Dependent Expression of Tissue Plasminogen Activator, a Pathogenicity Factor in Puumala Hantavirus Disease.

Hantaviruses are zoonotic viruses that show various degrees of vasculopathy in humans. In this study, we analyzed the regulation of 2 fibrinolytic parameters, tissue plasminogen activator (tPA) and its physiological inhibitor, plasminogen activator inhibitor 1 (PAI-1), in Puumala hantavirus (PUUV)-infected patients and in human microvascular endothelial cells. We detected strong upregulation of tPA in the acute phase of illness and in PUUV-infected macaques and found the tPA level to positively correlate with disease severity. The median levels of PAI-1 during the acute stage did not differ from those during the recovery phase. In concordance, hantaviruses induced tPA but not PAI-1 in microvascular endothelial cells, and the induction was demonstrated to be dependent on type I interferon. Importantly, type I and II interferons directly upregulated tPA through signal transducer and activator of transcription 1 (STAT1), which regulated tPA gene expression via a STAT1-responsive enhancer element. These results suggest that tPA may be a general factor in the immunological response to viruses.