Browsing by Subject "HEMORRHAGIC-FEVER"

Sort by: Order: Results:

Now showing items 1-20 of 25
  • Li, Sai; Rissanen, Ilona; Zeltina, Antra; Hepojoki, Jussi; Raghwani, Jayna; Harlos, Karl; Pybus, Oliver G.; Huiskonen, Juha T.; Bowden, Thomas A. (2016)
    Hantaviruses, a geographically diverse group of zoonotic pathogens, initiate cell infection through the concerted action of Gn and Gc viral surface glycoproteins. Here, we describe the high-resolution crystal structure of the antigenic ectodomain of Gn from Puumala hantavirus (PUUV), a causative agent of hemorrhagic fever with renal syndrome. Fitting of PUUV Gn into an electron cryomicroscopy reconstruction of intact Gn-Gc spike complexes from the closely related but non-pathogenic Tula hantavirus localized Gn tetramers to the membrane-distal surface of the virion. The accuracy of the fitting was corroborated by epitope mapping and genetic analysis of available PUUV sequences. Interestingly, Gn exhibits greater non-synonymous sequence diversity than the less accessible Gc, supporting a role of the host humoral immune response in exerting selective pressure on the virus surface. The fold of PUUV Gn is likely to be widely conserved across hantaviruses.
  • Koskela, Sirpa; Mäkelä, Satu; Strandin, Tomas; Vaheri, Antti; Outinen, Tuula; Joutsi-Korhonen, Lotta; Pörsti, Ilkka; Mustonen, Jukka; Laine, Outi (2021)
    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.
  • Ribas Salvador, Alexis; Guivier, Emmanuel; Xuereb, Anne; Chaval, Yannick; Cadet, Patrice; Poulle, Marie-Lazarine; Sironen, Tarja; Voutilainen, Liina; Henttonen, Heikki; Cosson, Jean-Francois; Charbonnel, Nathalie (2011)
  • Erra, Elina O.; Korhonen, Essi M.; Voutilainen, Liina; Huhtamo, Eili; Vapalahti, Olli; Kantele, Anu (2013)
  • Hautala, Timo; Partanen, Terhi; Sironen, Tarja; Rajaniemi, Saara-Mari; Hautala, Nina; Vainio, Olli; Vapalahti, Olli; Kauma, Heikki; Vaheri, Antti (2013)
  • 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.
  • 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.
  • 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.
  • Hepojoki, Jussi; Cabrera, Luz E.; Hepojoki, Satu; Bellomo, Carla; Kareinen, Lauri; Andersson, Leif C.; Vaheri, Antti; Mäkelä, Satu; Mustonen, Jukka; Vapalahti, Olli; Martinez, Valeria; Strandin, Tomas (2021)
    In humans, orthohantaviruses can cause hemorrhagic fever with renal syndrome (HFRS) or hantavirus pulmonary syndrome (HPS). An earlier study reported that acute Andes virus HPS caused a massive and transient elevation in the number of circulating plasmablasts with specificity towards both viral and host antigens suggestive of polyclonal B cell activation. Immunoglobulins (Igs), produced by different B cell populations, comprise heavy and light chains; however, a certain amount of free light chains (FLCs) is constantly present in serum. Upregulation of FLCs, especially clonal species, associates with renal pathogenesis by fibril or deposit formations affecting the glomeruli, induction of epithelial cell disorders, or cast formation in the tubular network. We report that acute orthohantavirus infection increases the level of Ig FLCs in serum of both HFRS and HPS patients, and that the increase correlates with the severity of acute kidney injury in HFRS. The fact that the kappa to lambda FLC ratio in the sera of HFRS and HPS patients remained within the normal range suggests polyclonal B cell activation rather than proliferation of a single B cell clone. HFRS patients demonstrated increased urinary excretion of FLCs, and we found plasma cell infiltration in archival patient kidney biopsies that we speculate to contribute to the observed FLC excreta. Analysis of hospitalized HFRS patients' peripheral blood mononuclear cells showed elevated plasmablast levels, a fraction of which stained positive for Puumala virus antigen. Furthermore, B cells isolated from healthy donors were susceptible to Puumala virus in vitro, and the virus infection induced increased production of Igs and FLCs. The findings propose that hantaviruses directly activate B cells, and that the ensuing intense production of polyclonal Igs and FLCs may contribute to acute hantavirus infection-associated pathological findings. Author summary Orthohantaviruses are globally spread zoonotic pathogens, which can cause hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS) with significant burden to human health. The pathogenesis mechanisms of orthohantavirus-caused diseases are not known in detail; however, excessive immune response towards the virus with concomitant pathological effects against host tissues appears to be a contributing factor. Here we report an increase of free immunoglobulin (Ig) light chains (FLCs), components required to make complete Ig molecules, in blood of acute HFRS and HPS. Samples collected during acute HFRS demonstrated increased FLCs levels in the urine and blood of patients hospitalized due the disease. Furthermore, the FLC levels positively correlated with markers of acute kidney injury. In addition, our results show that orthohantaviruses can infect and activate B cells to produce FLCs as well as whole Igs, which provides a mechanistic explanation of the increased FLC levels in patients. Taken together, our results suggest that aberrant antibody responses might play a role in the pathogenesis of orthantavirus infections.
  • 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)
  • Cabrera, Luz E.; Schmotz, Constanze; Saleem, Moin A.; Lehtonen, Sanna; Vapalahti, Olli; Vaheri, Antti; Mäkelä, Satu; Mustonen, Jukka; Strandin, Tomas (2022)
    Old-world orthohantaviruses cause hemorrhagic fever with renal syndrome (HFRS), characterized by acute kidney injury (AKI) with transient proteinuria. It seems plausible that proteinuria during acute HFRS is mediated by the disruption of the glomerular filtration barrier (GFB) due to vascular leakage, a hallmark of orthohantavirus-caused diseases. However, direct infection of endothelial cells by orthohantaviruses does not result in increased endothelial permeability, and alternative explanations for vascular leakage and diminished GFB function are necessary. Vascular integrity is partly dependent on an intact endothelial glycocalyx, which is susceptible to cleavage by heparanase (HPSE). To understand the role of glycocalyx degradation in HFRS-associated proteinuria, we investigated the levels of HPSE in urine and plasma during acute, convalescent and recovery stages of HFRS caused by Puumala orthohantavirus. HPSE levels in urine during acute HFRS were significantly increased and strongly associated with the severity of AKI and other markers of disease severity. Furthermore, increased expression of HPSE was detected in vitro in orthohantavirus-infected podocytes, which line the outer surfaces of glomerular capillaries. Taken together, these findings suggest the local activation of HPSE in the kidneys of orthohantavirus-infected patients with the potential to disrupt the endothelial glycocalyx, leading to increased protein leakage through the GFB, resulting in high amounts of proteinuria.
  • Clement, Jan; Ahlm, Clas; Avsic-Zupanc, Tatjana; Botten, Jason; Chandran, Kartik; Jonsson, Colleen B.; Kariwa, Hiroaki; Klingstrom, Jonas; Klempa, Boris; Krueger, Detlev H.; Leirs, Herwig; Li, Dexin; Liang, Mifang; Markotic, Alemka; Papa, Anna; Schmaljohn, Connie S.; Tischler, Nicole D.; Ulrich, Rainer G.; Vaheri, Antti; Vial, Cecilia; Yanagihara, Richard; Maes, Piet (2020)
    The 2019 11th International Conference on Hantaviruses (ICH 2019) was organized by the International Society for Hantaviruses (ISH), and held on September 1-4, 2019, at the Irish College, in Leuven, Belgium. These ICHs have been held every three years since 1989. ICH 2019 was attended by 158 participants from 33 countries. The current report summarizes research presented on all aspects of hantavirology: ecology; pathogenesis and immune responses; virus phylogeny, replication and morphogenesis; epidemiology; vaccines, therapeutics and prevention; and clinical aspects and diagnosis.
  • Papa, Anna; Vaheri, Antti; LeDuc, James W.; Krueger, Detlev H.; Avsic-Zupanc, Tatjana; Arikawa, Jiro; Song, Jin-Won; Markotic, Alemka; Clement, Jan; Liang, Mifang; Li, Dexin; Yashina, Liudmila N.; Jonsson, Colleen B.; Schmaljohn, Connie S. (2016)
    The 10th International Conference on Hantaviruses, organized by the International Society on Hantaviruses, was held from May 31-June 3, 2016 at Colorado State University, Fort Collins, CO, USA. These conferences have been held every three years since 1980. The current report summarizes research presented on all aspects of hantavirology: ecology and epidemiology, virus replication, phylogeny, pathogenesis, immune response, clinical studies, vaccines and therapeutics. (C) 2016 Elsevier B.V. All rights reserved.
  • 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.
  • Iheozor-Ejiofor, Rommel; Vapalahti, Katariina; Sironen, Tarja; Levanov, Lev; Hepojoki, Jussi; Lundkvist, Åke; Mäkelä, Satu; Vaheri, Antti; Mustonen, Jukka; Plyusnin, Alexander; Strandin, Tomas M.; Vapalahti, Olli (2022)
    Nephropathia epidemica (NE), a mild form of haemorrhagic fever with renal syndrome (HFRS), is an acute febrile illness caused by Puumala orthohantavirus (PUUV). NE manifests typically with acute kidney injury (AKI), with a case fatality rate of about 0.1%. The treatment and management of hantavirus infections are mainly supportive, although neutralizing monoclonal antibodies and immune sera therapeutics are under investigation. In order to assess the potential use of antibody therapeutics in NE, we sought to determine the relationship between circulating PUUV neutralizing antibodies, PUUV nucleocapsid protein (N) IgG antibodies, and viral loads with markers of disease severity. The study included serum samples of extensively characterized patient cohorts (n = 116) from Tampere University Hospital, Finland. The results showed that upon hospitalization, most patients already had considerable neutralizing and anti-PUUV-N IgG antibody levels. However, contrary to expectations, neutralizing antibody titers from the first day of hospitalization did not appear to protect from AKI or correlate with more favorable disease outcomes. This indicates that further studies are needed to investigate the applicability of neutralizing antibodies as a therapy for hospitalized NE patients.
  • Outinen, Tuula K.; Kuparinen, Taru; Jylhava, Juulia; Leppanen, Sonja; Mustonen, Jukka; Makela, Satu; Porsti, Ilkka; Syrjanen, Jaana; Vaheri, Antti; Hurme, Mikko (2012)
  • Outinen, Tuula K.; Tervo, Laura; Makela, Satu; Huttunen, Reetta; Maenpaa, Niina; Huhtala, Heini; Vaheri, Antti; Mustonen, Jukka; Aittoniemi, Janne (2013)
  • Douglas, Kirk Osmond; Samuels, Thelma Alafia; Iheozor-Ejiofor, Rommel; Vapalahti, Olli; Sironen, Tarja; Gittens-St. Hilaire, Marquita (2021)
    Background: Hantavirus pulmonary syndrome (HPS) is well-known in South and North America; however, not enough data exist for the Caribbean. The first report of clinical orthohantavirus infection was obtained in Barbados, but no other evidence of clinical orthohantavirus infections among adults in the Caribbean has been documented. Methods: Using enzyme linked immunosorbent assay (ELISA) tests followed by confirmatory testing with immunofluorescent assays (IFA), immunochromatographic (ICG) tests, and pseudotype focus reduction neutralization tests (pFRNT), we retrospectively and prospectively detected orthohantavirus-specific antibodies among patients with febrile illness in Barbados. Results: The orthohantavirus prevalence rate varied from 5.8 to 102.6 cases per 100,000 persons among febrile patients who sought medical attention annually between 2008 and 2016. Two major orthohantavirus epidemics occurred in Barbados during 2010 and 2016. Peak orthohantavis infections were observed observed during the rainy season (August) and prevalence rates were significantly higher in females than males and in patients from urban parishes than rural parishes. Conclusions: Orthohantavirus infections are still occurring in Barbados and in some patients along with multiple pathogen infections (CHIKV, ZIKV, DENV and Leptospira). Orthohantavirus infections are more prevalent during periods of high rainfall (rainy season) with peak transmission in August; females are more likely to be infected than males and infections are more likely among patients from urban rather than rural parishes in Barbados.
  • Outinen, Tuula K.; Mäkelä, Satu; Pörsti, Ilkka; Vaheri, Antti; Mustonen, Jukka (2022)
    Annually, over 10,000 cases of hemorrhagic fever with renal syndrome (HFRS) are diagnosed in Europe. Puumala hantavirus (PUUV) causes most of the European HFRS cases. PUUV causes usually a relatively mild disease, which is rarely fatal. However, the severity of the infection varies greatly, and factors affecting the severity are mostly unrevealed. Host genes are known to have an effect. The typical clinical features in PUUV infection include acute kidney injury, thrombocytopenia, and increased vascular permeability. The primary target of hantavirus is the endothelium of the vessels of different organs. Although PUUV does not cause direct cytopathology of the endothelial cells, remarkable changes in both the barrier function of the endothelium and the function of the infected endothelial cells occur. Host immune or inflammatory mechanisms are probably important in the development of the capillary leakage. Several immunoinflammatory biomarkers have been studied in the context of assessing the severity of HFRS caused by PUUV. Most of them are not used in clinical practice, but the increasing knowledge about the biomarkers has elucidated the pathogenesis of PUUV infection.