Browsing by Subject "Puumala virus"

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  • Castel, Guillaume; Couteaudier, Mathilde; Sauvage, Frank; Pons, Jean-Baptiste; Murri, Severine; Plyusnina, Angelina; Pontier, Dominique; Cosson, Jean-Francois; Plyusnin, Alexander; Marianneau, Philippe; Tordo, Noel (2015)
    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.
  • Niskanen, Silja; Jääskeläinen, Anne; Vapalahti, Olli; Sironen, Tarja (2019)
    Puumala virus (PUUV) is the most common cause of hantavirus infection in Europe, with thousands of cases occurring particularly in Northern, Central and Eastern Europe and Russia. It causes a mild form of hemorrhagic fever with renal syndrome also known as nephropathia epidemica (NE) with clinical picture ranging from mild to severe. Currently, the laboratory diagnosis of NE is mainly based on serology. Here, we evaluated a real-time one-step qRT-PCR (PUUV-qRT-PCR) for detection of PUUV with 238 consecutive diagnostic serum samples from patients with suspected PUUV infection. The PUUV-qRT-PCR was both specific and sensitive for PUUV RNA. The analytical sensitivity (limit of detection) was estimated to be four copies of PUUV per reaction. Altogether 28 out of 30 (93%) PUUV IgM positive samples were positive also for PUUV RNA. No false positives were detected and the specificity was thus 100%. Interestingly, one sample was found positive in PUUV-qRT-PCR prior to subsequent IgM and IgG seroconversion. PUUV-qRT-PCR could be used for diagnostics in the early phase of NE infection and might be helpful especially in the rare severe cases when the patient's condition may deteriorate rapidly.
  • Niskanen, Silja; Jääskeläinen, Anne; Sironen, Tarja; Vapalahti, Olli (Helsingfors universitet, 2016)
    Myyräkuume on Puumala-viruksen aiheuttama munuaisoireinen verenvuotokuume, jonka oirekuva vaihtelee lievästä vakavaan. Puumala-virus kuuluu jyrsijöiden, hyönteissyöjien ja lepakoiden levittämiin hantaviruksiin, jotka aiheuttavat munuaisoireista verenvuotokuumetta Euroopassa ja Aasiassa ja hantavirus-sydän-keuhko-oireyhtymää Amerikan mantereella. Puumala on Euroopan yleisin hantavirus ja sitä tavataan Pohjois-, Keski- ja Itä-Euroopassa ja Venäjällä. Sen kantajana toimii metsämyyrä (Myodes glareolus), jonka kannan vaihteluita myyräkuumeinsidenssi seuraa ollen noin 560–3800 vuosittain. Suomalaisista noin 5 % on Puumala-seropositiivisia, joskin luku on jopa 11 % Itä-Suomessa. Myyräkuumeen itämisaika on noin kahdesta neljään viikkoa. Tauti alkaa äkillisesti kuumeella ja päänsäryllä, joita seuraavat vatsa- ja selkäkivut, pahoinvointi ja oliguria. Taudin alussa noin kolmasosalla esiintyy myopiaa, joka on patognomonista myyräkuumeelle. Verenkuvassa näkyvät kohonnut CRP ja leukosyytit sekä trombosytopenia. 0,1 % potilaista menehtyy ja kuolinsyynä on useimmiten verenvuotoshokki tai aivolisäkkeen verenvuoto. 5 % potilaista päätyy dialyysiin ja jotkut kärsivät useamman vuoden ajan taudin sairastamisen jälkeen kohonneista verenpainearvoista. Myyräkuumeen laboratoriodiagnostiikka perustuu tällä hetkellä IgM-luokan vasta-aineiden osoittamiseen verestä. Potilaat serokonvertoituvat jo taudin ensimmäisinä päivänä, joten serologia on varsin käyttökelpoinen diagnostisena menetelmänä. Halusimme kuitenkin selvittää, onko myyräkuumetta mahdollista diagnosoida reaaliaikaisella PCR-testillä, joka osoittaisi Puumala-viruksen RNA:ta ja viremian potilaan verestä jo aivan taudin alkuvaiheessa. Keräsimme yhteensä 238 seeruminäytettä, jotka oli lähetetty HUSLAB-laboratorioon eri sairaaloista ja terveyskeskuksista rutiininomaista myyräkuumediagnostiikkaa varten. Lisäksi tutkittiin muille hantaviruksille positiiviset näytteet (Saaremaa, Tula, Tobografov, Dobrava ja Hantaan) sekä 20 negatiivista kontrollinäytettä. Näytteet tutkittiin rutiininomaisen IgM-testin lisäksi sekä kehittämällämme reaaliaikaisella qRT-PCR-menetelmällä (PUUV-qRT-PCR) että kaksivaiheisella RT-nested-PCR-menetelmällä, josta positiiviset näytteet lähetettiin eteenpäin sekvensoitaviksi. qRT-PCR-menetelmässä standardinäytteenä toimi Sotkamo-kannan RNA:n S-juoste. Diagnostiikassa positiivisiksi osoittautui 31 näytettä. Näistä 30 oli positiivisia serologisella menetelmällä. Yksi näyte jäi siis positiiviseksi ainoastaan PUUV-qRT-PCR:ssä. 30 IgM-positiivisesta näytteestä 28 oli positiivisia PUUV-qRT-PCR-menetelmällä. Diagnostinen sensitiivisyys oli 93.3% (95% CI: 77.93%-99.18%). Tutkimme positiivisen näytteen antaneiden potilaiden tiedot HUSLAB:n potilastietokannasta. Kävi ilmi, että vasta-ainenegatiivisesta, PUUV-qRT-PCR-positiivisen näytteen antaneesta potilaasta oli otettu näyte jo aivan taudin alkuvaiheissa, jolloin viremia on korkealla tasolla, mutta IgM-luokan vasta-aineet eivät ole vielä nousseet. Kyseisestä potilaasta otettiin vielä myöhemmin toinen näyte, joka oli positiivinen sekä IgM-testillä että PUUV-qRT-PCR-menetelmällä. Kaksi PUUV-qRT-PCR-menetelmällä negatiiviseksi jäänyttä IgM-positiivista potilasta oli puolestaan tutkittu 1-2 viikkoa oireiden alusta, jolloin viremia oli jo näin ollen ehtinyt laskea. Kaksivaiheisella RT-nested-PCR-menetelmällä tutkittuna 25 näytteestä oli osoitettavissa Puumala-viruksen RNA:ta. Nämä näytteet sekvensoitiin ja kannat järjestettiin fylogeeniseen puuhun eri suomalaisten kantojen oheen, mikä osoitti PCR-menetelmän löytävän varsin laajasti suomalaisia Puumala-viruskantoja. Negatiiviset kontrollinäytteet ja muille hantaviruksille positiiviset näytteet jäivät PCR-menetelmillä negatiivisiksi, joten menetelmän spesifisyys oli 100 %. Reaaliaikainen qRT-PCR-testi osoittautui sekä herkäksi että tarkaksi ja voisi toimia diagnostiikassa täydentävänä tutkimuksena serologisten menetelmien ohella. Se voisi joissain tapauksissa osittaa taudin jo ennen vasta-aineiden ilmaantumista. Haasteita viruksen RNA:n osoittamiselle diagnostiikassa asettaa Puumalan varsin suuri geneettinen varianssi. Todennäköisesti testimme on varsin spesifinen suomalaisille kannoille, mutta tutkimuksia erilaisilla Puumala-kannoilla tarvitaan vielä. Vastaavia tuloksia on saatu kahdessa ruotsalaistutkimuksessa, jossa reaaliaikainen PCR-testi osoittautui herkäksi ja tarkaksi, mutta varsin spesifiseksi ruotsalaisille kannoille.
  • 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)
  • 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.
  • Lamponen, Tiitus; Hetemäki, Iivo; Niemi, Heikki J.; Jarva, Hanna; Kekäläinen, Eliisa; Mäkelä, Satu; Mustonen, Jukka; Vaheri, Antti; Arstila, T. Petteri (2021)
    Persistence of immune memory in humans is a crucial yet poorly understood aspect of immunology. Here we have studied the effect of Puumala hantavirus infection on unrelated, pre-existing immune memory by studying T cell- and antibody responses against toxoid vaccine antigens of diphtheria, tetanus and pertussis in a cohort of 45 patients. We found that tetanus- and pertussis-specific IgG concentrations elevate during acute Puumala virus infection. Increase in vaccine IgG was associated with proliferation of heterologous T cells. Interestingly, increases in tetanus-specific IgG persisted a year after the infection while pertussis-specific IgG declined rapidly; a difference in IgG kinetics resembling the difference seen after vaccination against tetanus and pertussis. These results suggest that persistence of immune memory is facilitated by heterologous boosting of old memory during memory formation against newly encountered antigens. They also show that different toxoid antigens may be treated differently. Our study gives new insight into how immune memory formation may alter pre-existing immune memory, and also shows that heterologous immunity may have an impact on vaccination outcomes. (C) 2021 Elsevier Ltd. All rights reserved.
  • Charbonnel, Nathalie; Pages, Marie; Sironen, Tarja; Henttonen, Heikki; Vapalahti, Olli; Mustonen, Jukka; Vaheri, Antti (2014)
  • Mustonen, Jukka; Strandin, Tomas; Mäkelä, Satu; Vaheri, Antti (2020)
    Myyräkuume on Puumala-viruksen (PUUV) aiheuttama zoonoosi. Tärkeitä tekijöitä ihmisen immuuni-vasteessa virukselle ovat ainakin neutrofiiliset granulosyytit ja sytotoksiset tappaja-T-solut, joiden suhteettoman voimakas aktivaatio saattaa johtaa endoteelivaurioon. Lisääntynyt kapillaarivuoto, fibrinolyysi ja komplementin aktivaatio kuuluvat taudin patogeneesiin. Akuutin munuaisvaurion vaikeutta ennustaa hyvin taudin alkuvaiheessa otetun virtsan seulontatestin tulos. Trombosytopenian synnyssä keskeistä ovat trombosyyttien ja endoteelisolujen interaktio. Ohimenevät EKG-muutokset sekä bradykardia ovat tavallisia löydöksiä. Kroonisten hormonivajausten kehittyminen on mahdollista. Spesifistä hoitoa ei ole olemassa, mutta bradykiniinireseptorin estäjä ikatibantti saattaa olla tehokas lääke hyvin vaikeasti sairaiden potilaiden hoitona.
  • Savolainen, Kia (Helsingin yliopisto, 2019)
    Co-­infection, a state in which the host is infected with more than one micro-­ or macroparasite at a time, is the norm in the wild because of a wide range of interacting organisms and parasites. Bank vole is a reservoir host of Puumala hantavirus (PUUV), a pathogen causing Nephropathia Endemica, an endemic disease in Finland. The helper T cell (Th)1/Th2 polarization theory, which is established in the laboratory, but less-­studied in the wild, suggests that there is a trade-­off between Th1 response against microparasites and Th2 response against macroparasites. I studied whether helminth or hantavirus infection, individually and synergistically, have effect on the immune responses of wild bank voles and whether there is a trade-­off between Th1 and Th2 responses. My hypothesis was that helminth infection would reduce the bank voles’ ability to mount an effective immune response against viral infections and make them more susceptible to chronic Puumala virus infection. I measured mRNA levels of transcription factors Tbet (Th1 response) and Gata3 (Th2 response) in the splenocytes of wild-­caught bank voles after stimulating the cells with different immune stimulants. I also measured the constitutive levels of Tbet and Gata3 in bank voles’ spleens. The splenocytes of PUUV-­infected bank voles were less responsive to stimulations than those of PUUV-­negative ones. The reduced ability of splenocytes from PUUV-­infected voles to respond to stimulation can be because of the virus itself affecting the T cell function or alternatively due to an inherent defect in immune cells making them more susceptible to PUUV infection. The constitutive expression of Gata3 in spleen correlated positively with gastrointestinal nematode load in PUUV-­infected voles but not in PUUV-­negative voles. This can be because of mounting an immune response against helminths reduces the bank voles’ ability to resist the viral infection in accordance with the trade-­off between Th1 and Th2 responses or as previous studies have shown, Gata3 can act as a marker of infection tolerance in bank voles. Because of a small sample size and a heterologous group of studied bank voles, more research is needed on co-­infection immunology in bank voles and other wild animals.
  • Mustonen, Jukka; Vaheri, Antti (2018)
    Hantavirusten aiheuttamat ¬infektiot eroavat toisistaan taudinkuvaltaan ja vaikeudeltaan.
  • Reijniers, Jonas; Tersago, Katrien; Borremans, Benny; Hartemink, Nienke; Voutilainen, Liina; Henttonen, Heikki; Leirs, Herwig (2020)
    For wildlife diseases, one often relies on host density to predict host infection prevalence and the subsequent force of infection to humans in the case of zoonoses. Indeed, if transmission is mainly indirect, i.e., by way of the environment, the force of infection is expected to increase with host density, yet the laborious field data supporting this theoretical claim are often absent. Hantaviruses are among those zoonoses that have been studied extensively over the past decades, as they pose a significant threat to humans. In Europe, the most widespread hantavirus is the Puumala virus (PUUV), which is carried by the bank vole and causes nephropathia epidemica (NE) in humans. Extensive field campaigns have been carried out in Central Finland to shed light on this supposed relationship between bank vole density and PUUV prevalence and to identify other drivers for the infection dynamics. This resulted in the surprising observation that the relationship between bank vole density and PUUV prevalence is not purely monotonic on an annual basis, contrary to what previous models predicted: a higher vole density does not necessary result in a higher infection prevalence, nor in an increased number of humans reported having NE. Here, we advance a novel individual-based spatially-explicit model which takes into account the immunity provided by maternal antibodies and which simulates the spatial behavior of the host, both possible causes for this discrepancy that were not accounted for in previous models. We show that the reduced prevalence in peak years can be attributed to transient immunity, and that the density-dependent spatial vole behavior, i.e., the fact that home ranges are smaller in high density years, plays only a minor role. The applicability of the model is not limited to the study and prediction of PUUV (and NE) occurrence in Europe, as it could be easily adapted to model other rodent-borne diseases, either with indirect or direct transmission.