Browsing by Subject "hantavirus"

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  • Rusanen, Juuso (Helsingin yliopisto, 2019)
    Nopeat ja luotettavat testit neutraloivien vasta-aineiden tunnistamiseen olisivat hyödyksi suojaavan immuni-teetin määrittämisessä ja hyvin lähisukuisten taudinaiheuttajien aikaansaamien tartuntatautien serologisessa erottamisessa toisistaan. Olemme aiemmin kehittäneet aikaerotteiseen Försterin resonanssienergiansiirtoon (TR-FRET) perustuvia nopeita immuunimäärityksiä ja osoittaneet niiden toimivan erinomaisen hyvin myyrä-kuumeen diagnostiikassa. Pidimme mahdollisena, että näitä TR-FRET-immuunimääritysmenetelmiä voitaisiin käyttää myös neutraloivien vasta-aineiden tunnistamiseen. Selvittääksemme tämän Puumala-virusta hyväksi käyttäen pystytimme kaksi TR-FRETiin perustuvaa määritysmenetelmää vasta-aineille, jotka tunnistavat kyseisen viruksen ulkorakenteeseen kuuluvan Gn-glykoproteiinin ektodomeenin (GnE): GnE-CFRET (kompeti-tiivinen FRET-immunomääritys) ja GnE-LFRET (proteiini L:ään perustuva FRET-immunomääritys). Analy-soimme näillä menetelmillä 42 seeruminäytettä, mukaan lukien 28 näytettä aiemmin myyräkuumeen sairas-taneilta potilailta, ja määritimme vastaavat neutralisaatiotiitterit pFRNT-menetelmällä (pseudotype focus re-duction neutralization test). GnE-LFRET–signaalin ja neutralisaatiotiitterin välillä oli selkeä korrelaatio mene-telmän tunnistaessa vahvasti neutraloivat näytteet suurella herkkyydellä ja tarkkuudella. Myös GnE-CFRET tunnisti vahvasti neutraloivat näytteet tarkasti, joskaan ei ollut yhtä herkkä. Jatkossa neutraloivien vasta-aineiden tunnistusta TR-FRET–menetelmillä voidaan kehittää käyttämällä useampia eri leimattuja neutra-loivia vasta-aineita ja useampia eri leimattuja antigeenejä. Ihanteellisesti leimattuna antigeeninä voitaisiin käyttää kokonaista glykoproteiinipiikkikompleksia tai viruksen kaltaista partikkelia (VLP). Yhteenvetona TR-FRET-immuunimääritykset vaikuttavat lupaavilta neutraloivien vasta-aineiden tunnistuksessa, mutta lisää kehitystyötä tarvitaan ennen kuin tämä uusi lähestymistapa on valmis kenttäkäyttöön.
  • Bellomo, Carla; Korva, Misa; Papa, Anna; Mäkelä, Satu; Mustonen, Jukka; Avsic-Zupanc, Tatjana; Vaheri, Antti; Martinez, Valeria P.; Strandin, Tomas (2018)
    We analyzed the levels of circulating tissue plasminogen activator (tPA) and plasminogen activator inhibitor (PAI)-1 in acute hantavirus cardiopulmonary syndrome (HCPS) and hemorrhagic fever with renal syndrome (HFRS). The levels of tPA commonly increased in both diseases, whereas PAI-1 correlated with disease severity in HCPS but not in HFRS.
  • Koskela, Sirpa M.; Joutsi-Korhonen, Lotta; Mäkelä, Satu M.; Huhtala, Heini; Vaheri, Antti I.; Pörsti, Ilkka; Mustonen, Jukka T.; Laine, Outi K. (2018)
    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. Copyright (C) 2018 Wolters Kluwer Health, Inc. All rights reserved.
  • Mull, Nathaniel; Jackson, Reilly; Sironen, Tarja; Forbes, Kristian M. (2020)
    The number of documented American orthohantaviruses has increased significantly over recent decades, but most fundamental research has remained focused on just two of them: Andes virus (ANDV) and Sin Nombre virus (SNV). The majority of American orthohantaviruses are known to cause disease in humans, and most of these pathogenic strains were not described prior to human cases, indicating the importance of understanding all members of the virus clade. In this review, we summarize information on the ecology of under-studied rodent-borne American orthohantaviruses to form general conclusions and highlight important gaps in knowledge. Information regarding the presence and genetic diversity of many orthohantaviruses throughout the distributional range of their hosts is minimal and would significantly benefit from virus isolations to indicate a reservoir role. Additionally, few studies have investigated the mechanisms underlying transmission routes and factors affecting the environmental persistence of orthohantaviruses, limiting our understanding of factors driving prevalence fluctuations. As landscapes continue to change, host ranges and human exposure to orthohantaviruses likely will as well. Research on the ecology of neglected orthohantaviruses is necessary for understanding both current and future threats to human health.
  • Laine, Outi; Joutsi-Korhonen, Lotta; Lassila, Riitta; Huhtala, Heini; Vaheri, Antti; Makela, Satu; Mustonen, Jukka (2016)
    We evaluated the mechanisms of thrombocytopenia and procoagulant changes in relation with clinical variables in a cohort of patients with acute hantavirus disease. Blood samples of 33 prospectively recruited, consecutive, hospitalized patients with acute Puumala virus-induced hemorrhagic fever with renal syndrome (HFRS) were collected acutely and at the recovery visit (control). Serum thrombopoietin (TPO) and activity of plasma microparticles (MPs) from various cell sources were measured with enzyme-linked immunosorbent assay-based methods. The results were related to data on platelet indices and functions, coagulation variables, and clinical disease. Serum TPO was nearly 4-fold higher acutely compared with the control (median 207pg/mL, range 56-1258pg/mL vs. median 58 pg/mL, range 11-241pg/mL, P Upregulated TPO together with high MPV and IPF% confirm active thrombopoiesis, but do not predict severity of HFRS. Simultaneously, elevated prothrombin fragments and D-dimer suggest increased consumption of platelets in patients with severe AKI. Activity of platelet-derived MPs in HFRS should be studied with flow cytometry in a larger cohort of patients.
  • Sironen, Tarja; Sane, Jussi; Lokki, Marja-Liisa; Meri, Seppo; Andersson, Leif C.; Hautala, Timo; Kauma, Heikki; Vuorinen, Sakari; Rasmuson, Johan; Evander, Magnus; Ahlm, Clas; Vaheri, Antti (2017)
    The case-fatality rate of hantavirus disease depends strongly on the causative hantavirus, ranging from 0.1% to 40%. However, the pathogenesis is not fully understood, and at present no licensed therapies exist. We describe fatal cases caused by Puumala hantavirus indicating involvement of complement activation and vascular leakage.
  • Mantula, Paula; Tietavainen, Johanna; Clement, Jan; Niemelä, Onni; Pörsti, Ilkka; Vaheri, Antti; Mustonen, Jukka; Mäkelä, Satu; Outinen, Tuula (2020)
    Transient proteinuria and acute kidney injury (AKI) are characteristics of Puumala virus (PUUV) infection. Albuminuria peaks around the fifth day and associates with AKI severity. To evaluate albuminuria disappearance rate, we quantified albumin excretion at different time points after the fever onset. The study included 141 consecutive patients hospitalized due to acute PUUV infection in Tampere University Hospital, Finland. Timed overnight albumin excretion (cU-Alb) was measured during the acute phase in 133 patients, once or twice during the convalescent phase within three months in 94 patients, and at six months in 36 patients. During hospitalization, 30% of the patients had moderately increased albuminuria (cU-Alb 20-200 mu g/min), while 57% presented with severely increased albuminuria (cU-Alb >200 mu g/min). Median cU-Alb was 311 mu g/min (range 2.2-6460)
  • Ling, Jiaxin; Verner-Carlsson, Jenny; Eriksson, Per; Plyusnina, Angelina; Loehmus, Mare; Jaerhult, Josef D.; van de Goot, Frank; Plyusnin, Alexander; Lundkvist, Ake; Sironen, Tarja (2019)
    Seoul virus (SEOV) is the etiologic agent of hemorrhagic fever with renal syndrome. It is carried by brown rats (Rattus norvegicus), a commensal rodent that closely cohabitates with humans in urban environments. SEOV has a worldwide distribution, and in Europe, it has been found in rats in UK, France, Sweden, and Belgium, and human cases of SEOV infection have been reported in Germany, UK, France, and Belgium. In the search of hantaviruses in brown rats from the Netherlands, we found both serological and genetic evidence for the presence of SEOV in the local wild rat population. To further decipher the relationship with other SEOV variants globally, the complete genome of SEOV in the Netherlands was recovered. SEOV sequences obtained from three positive rats (captured at close trapping locations at the same time) were found highly similar. Phylogenetic analyses demonstrated that two lineages of SEOV circulate in Europe. Strains from the Netherlands and UK, together with the Baxter strain from US, constitute one of these two, while the second includes strains from Europe and Asia. Our results support a hypothesis of diverse routes of SEOV spread into Europe. These findings, combined with other indications on the expansion of the spatial European range of SEOV, suggest an increased risk of this virus for the public health, highlighting the need for increased surveillance.
  • Tietavainen, Johanna; Mantula, Paula; Outinen, Tuula; Huhtala, Heini; Porsti, Ilkka H.; Niemela, Onni; Vaheri, Antti; Makela, Satu; Mustonen, Jukka (2019)
    Introduction: Puumala hantavirus (PUUV) causes a mild type of hemorrhagic fever with renal syndrome characterized by acute kidney injury (AKI), increased capillary leakage, and thrombocytopenia. Albuminuria and hematuria in dipstick urine test at hospital admission are known to predict the severity of upcoming AKI. Methods: We analyzed dipstick urine glucose in 195 patients with acute PUUV infection at hospital admission, and divided them into 2 categories according to the presence or absence of glucose in the dipstick urine test. Determinants of disease severity were analyzed in glucosuric and nonglucosuric patients. Results: Altogether, 24 of 195 patients (12%) had glucosuria. The patients with glucosuria had more severe AKI than patients without glucosuria (median maximum creatinine concentration 459 mmol/l, range 78-1041 mmol/l vs. 166 mmol/l, range 51-1499 mmol/l; P <0.001). The glucosuric patients had more severe thrombocytopenia (median minimum platelet count 41 x 10(9)/l, range 5-102 x 10(9)/l vs. 62 x 10(9)/l, range 3249 x 10(9)/l; P = 0.006), and more pronounced signs of increased capillary leakage (change in weight, maximum plasma hematocrit, minimum plasma albumin). The glucosuric patients were more often in clinical shock at admission (20.8% vs. 1.2%; P <0.001) and the length of hospital stay was longer (median 7.5 days, range 4-22 days vs. 6 days, range 2-30 days; P = 0.009). Conclusion: Glucosuria is relatively rare, but when present it predicts a more severe disease course in patients with acute PUUV infection.
  • Outinen, Tuula K.; Mantula, Paula; Jaatinen, Pia; Hämäläinen, Mari; Moilanen, Eeva; Vaheri, Antti; Huhtala, Heini; Mäkelä, Satu; Mustonen, Jukka (2019)
    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.
  • Vaheri, Antti; Henttonen, Heikki; Mustonen, Jukka (2021)
    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.
  • Partanen, Terhi; Chen, Jie; Lehtonen, Johanna; Kuismin, Outi; Rusanen, Harri; Vapalahti, Olli; Vaheri, Antti; Anttila, Veli-Jukka; Bode, Michaela; Hautala, Nina; Vuorinen, Tytti; Glumoff, Virpi; Kraatari, Minna; Åström, Pirjo; Saarela, Janna; Kauma, Heikki; Lorenzo, Lazaro; Casanova, Jean-Laurent; Zhang, Shen-Ying; Seppänen, Mikko; Hautala, Timo (2020)
    Puumala hantavirus (PUUV) hemorrhagic fever with renal syndrome (HFRS) is common in Northern Europe; this infection is usually self-limited and severe complications are uncommon. PUUV and other hantaviruses, however, can rarely cause encephalitis. The pathogenesis of these rare and severe events is unknown. In this study, we explored the possibility that genetic defects in innate anti-viral immunity, as analogous to Toll-like receptor 3 (TLR3) mutations seen in HSV-1 encephalitis, may explain PUUV encephalitis. We completed exome sequencing of seven adult patients with encephalitis or encephalomyelitis during acute PUUV infection. We found heterozygosity for the TLR3 p.L742F novel variant in two of the seven unrelated patients (29%,p = 0.0195). TLR3-deficient P2.1 fibrosarcoma cell line and SV40-immortalized fibroblasts (SV40-fibroblasts) from patient skin expressing mutant or wild-type TLR3 were tested functionally. The TLR3 p.L742F allele displayed low poly(I:C)-stimulated cytokine induction when expressed in P2.1 cells. SV40-fibroblasts from three healthy controls produced increasing levels of IFN-lambda and IL-6 after 24 h of stimulation with increasing concentrations of poly(I:C), whereas the production of the cytokines was impaired in TLR3 L742F/WT patient SV40-fibroblasts. Heterozygous TLR3 mutation may underlie not only HSV-1 encephalitis but also PUUV hantavirus encephalitis. Such possibility should be further explored in encephalitis caused by these and other hantaviruses.
  • Charbonnel, Nathalie; Pages, Marie; Sironen, Tarja; Henttonen, Heikki; Vapalahti, Olli; Mustonen, Jukka; Vaheri, Antti (2014)
  • Rissanen, Ilona; Stass, Robert; Krumm, Stefanie A.; Seow, Jeffrey; Hulswit, Ruben J.G.; Paesen, Guido C.; Hepojoki, Jussi; Vapalahti, O.; Lundkvist, Åke; Reynard, Olivier; Volchkov, Viktor; Doores, Katie J.; Huiskonen, Juha T.; Bowden, Thomas A. (2020)
    The intricate lattice of Gn and Gc glycoprotein spike complexes on the hantavirus envelope facilitates host-cell entry and is the primary target of the neutralizing antibody-mediated immune response. Through study of a neutralizing monoclonal antibody termed mAb P-4G2, which neutralizes the zoonotic pathogen Puumala virus (PUUV), we provide a molecular-level basis for antibody-mediated targeting of the hantaviral glycoprotein lattice. Crystallographic analysis demonstrates that P-4G2 binds to a multi-domain site on PUUV Gc and may preclude fusogenic rearrangements of the glycoprotein that are required for host-cell entry. Furthermore, cryo-electron microscopy of PUUV-like particles in the presence of P-4G2 reveals a lattice-independent configuration of the Gc, demonstrating that P-4G2 perturbs the (Gn-Gc)4 lattice. This work provides a structure-based blueprint for rationalizing antibody-mediated targeting of hantaviruses.
  • Strandin, Tomas; Mäkelä, Satu; Mustonen, Jukka; Vaheri, Antti (2018)
    Hantaviruses cause hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS) in humans. Both diseases are considered to be immunologically mediated but the exact pathological mechanisms are still poorly understood. Neutrophils are considered the first line of defense against invading microbes but little is still known of their role in virus infections. We wanted to study the role of neutrophils in HFRS using blood and tissue samples obtained from Puumala hantavirus (PUUV)-infected patients. We found that neutrophil activation products myeloperoxidase and neutrophil elastase, together with interleukin-8 (the major neutrophil chemotactic factor in humans), are strongly elevated in blood of acute PUUV-HFRS and positively correlate with kidney dysfunction, the hallmark clinical finding of HFRS. These markers localized mainly in the tubulointerstitial space in the kidneys of PUUV-HFRS patients suggesting neutrophil activation to be a likely component of the general immune response toward hantaviruses. We also observed increased levels of circulating extracellular histones at the acute stage of the disease supporting previous findings of neutrophil extracellular trap formation in PUUV-HFRS. Mechanistically, we did not find evidence for direct PUUV-mediated activation of neutrophils but instead primary blood microvascular endothelial cells acquired a pro-inflammatory phenotype and promoted neutrophil degranulation in response to PUUV infection in vitro. These results suggest that neutrophils are activated by hantavirus-infected endothelial cells and may contribute to the kidney pathology which determines the severity of HFRS.
  • Sane, J.; Ollgren, J.; Makary, P.; Vapalahti, O.; Kuusi, M.; Lyytikainen, O. (2016)
    Puumala hantavirus (PUUV) causes haemorrhagic fever with renal syndrome in humans, an endemic disease in Finland. We aimed to study recent trends in PUUV infections in Finland, to evaluate whether there are regional differences in seasonality and long-term cycles and whether the patterns have changed over time. We analysed serologically confirmed acute PUUV infections reported to the National Infectious Disease Register from 1 April 1995 to 31 March 2014. A total of 30 942 cases of PUUV infections were identified during the study period. The average annual incidence was 31 cases/100 000 person-years with the highest in Eastern Finland and the lowest in Southwestern Finland. Throughout Finland there was not an increasing trend in incidence but changes in incidence, seasonality and long-term cycles differed regionally. Long-term cycles supported by high Bayesian posterior probabilities (73-100%) differed between the south and the north, shifting from 3 to 4 years, respectively. Temporal changes in seasonality were most prominent in Southwestern Finland. The pattern of human PUUV infection epidemiology probably primarily reflects the spatio-temporal interaction between bank-vole population dynamics and climate.
  • Rissanen, Ilona; Stass, Robert; Zeltina, Antra; Li, Sai; Hepojoki, Jussi; Harlos, Karl; Gilbert, Robert J. C.; Huiskonen, Juha T.; Bowden, Thomas A. (2017)
    Hantaviruses are zoonotic pathogens that cause severe hemorrhagic fever and pulmonary syndrome. The outer membrane of the hantavirus envelope displays a lattice of two glycoproteins, Gn and Gc, which orchestrate host cell recognition and entry. Here, we describe the crystal structure of the Gn glycoprotein ectodomain from the Asiatic Hantaan virus (HTNV), the most prevalent pathogenic hantavirus. Structural overlay analysis reveals that the HTNV Gn fold is highly similar to the Gn of Puumala virus (PUUV), a genetically and geographically distinct and less pathogenic hantavirus found predominantly in northeastern Europe, confirming that the hantaviral Gn fold is architecturally conserved across hantavirus clades. Interestingly, HTNV Gn crystallized at acidic pH, in a compact tetrameric configuration distinct from the organization at neutral pH. Analysis of the Gn, both in solution and in the context of the virion, confirms the pH-sensitive oligomeric nature of the glycoprotein, indicating that the hantaviral Gn undergoes structural transitions during host cell entry. These data allow us to present a structural model for how acidification during endocytic uptake of the virus triggers the dissociation of the metastable Gn-Gc lattice to enable insertion of the Gc-resident hydrophobic fusion loops into the host cell membrane. Together, these data reveal the dynamic plasticity of the structurally conserved hantaviral surface. IMPORTANCE Although outbreaks of Korean hemorrhagic fever were first recognized during the Korean War (1950 to 1953), it was not until 1978 that they were found to be caused by Hantaan virus (HTNV), the most prevalent pathogenic hantavirus. Here, we describe the crystal structure of HTNV envelope glycoprotein Gn, an integral component of the Gn-Gc glycoprotein spike complex responsible for host cell entry. HTNV Gn is structurally conserved with the Gn of a genetically and geographically distal hantavirus, Puumala virus, indicating that the observed alpha/beta fold is well preserved across the Hantaviridae family. The combination of our crystal structure with solution state analysis of recombinant protein and electron cryo-microscopy of acidified hantavirus allows us to propose a model for endosome-induced reorganization of the hantaviral glycoprotein lattice. This provides a molecular-level rationale for the exposure of the hydrophobic fusion loops on the Gc, a process required for fusion of viral and cellular membranes.
  • Luiskari, Piia (University of Helsinki, 1997)
  • Hepojoki, Jussi; Vaheri, Antti; Strandin, Tomas (2014)