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Tiberti N, Castilletti C, Gobbi FG. Extracellular vesicles in arbovirus infections: from basic biology to potential clinical applications. Front Cell Infect Microbiol 2025; 15:1558520. [PMID: 40357393 PMCID: PMC12066795 DOI: 10.3389/fcimb.2025.1558520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Accepted: 04/04/2025] [Indexed: 05/15/2025] Open
Abstract
Arthropod-borne viruses, or arboviruses, are currently considered a global health threat responsible for potentially severe human diseases. The increased population density, changes in land use and climate change are some of the factors that are contributing to the spread of these infections over the last years. The pathogenesis of these diseases and the mechanisms of interaction with the host, especially those leading to the development of severe forms, are yet to be fully understood. In recent years extracellular vesicles (EVs) have emerged as important players in the inter-cellular and host-pathogen interaction arising a lot of interest also in the field of vector-borne viruses. In this context, EVs seem to play a dual role, by either promoting, thus facilitating, or preventing infection. Many studies are showing how viruses can hijack the vesiculation machinery to escape the host immune response and exploit EVs to sustain their replication and propagation, even though EVs shed by immune cells seem essential to promote antiviral responses. In this manuscript we reviewed the current knowledge regarding the association between EVs and vector-borne viruses, paying particular attention to their possible role in disease transmission and dissemination, as well as to their potential as novel tools for clinical applications, spanning from biomarkers of clinical utility to novel therapeutic options.
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Affiliation(s)
- Natalia Tiberti
- Department of Infectious, Tropical Diseases and Microbiology, IRCCS Sacro Cuore Don Calabria Hospital, Negrar di Valpolicella, Verona, Italy
| | - Concetta Castilletti
- Department of Infectious, Tropical Diseases and Microbiology, IRCCS Sacro Cuore Don Calabria Hospital, Negrar di Valpolicella, Verona, Italy
| | - Federico Giovanni Gobbi
- Department of Infectious, Tropical Diseases and Microbiology, IRCCS Sacro Cuore Don Calabria Hospital, Negrar di Valpolicella, Verona, Italy
- Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
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Bago J, Bjedov L, Vucelja M, Tomljanović K, Cetinić Balent N, Zember S, Margaletić J, Đaković Rode O. The Influence of Biogeographic Diversity, Climate and Wildlife on the Incidence of Tick-Borne Encephalitis in Croatia. Viruses 2025; 17:266. [PMID: 40007021 PMCID: PMC11860385 DOI: 10.3390/v17020266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2025] [Revised: 01/31/2025] [Accepted: 02/11/2025] [Indexed: 02/27/2025] Open
Abstract
Tick-borne encephalitis (TBE) is a common arbovirus infection in Croatia. The aim of the study was to analyse 17 years of data on TBE seroprevalence and acute TBE cases in correlation with winter temperature, precipitation and wildlife abundance to identify possible patterns that may be predictive indicators of TBE incidence. Clinical diagnosis of TBE was confirmed by determining IgM and IgG anti-TBE antibodies. Of the 19,094 analysed patients, 4.2% had acute TBE, significantly more often in older age (p < 0.001) and male gender (p < 0.001). Overall seroprevalence of TBE among the tested population was 5.8% and varied annually from 2.8% to 10.7%. The mean acute TBE incidence rate was 1.1/100,000 population with significant regional differences: 1.7/100,000 in the continental vs. 0.2/100,000 and 0.5/100,000 in the Mediterranean and Alpine regions, respectively. A particularly high incidence of 3.1/100,000 was recorded in northern Croatia. TBE displayed a seasonal pattern, peaking in June and July. Moderate negative correlations were observed between TBE acute cases and winter temperatures from December to February (r = -0.461; p = 0.062), relative rodent abundance (r = -0.414; p = 0.098) and yearly precipitation from one year before (r = -0.401; p = 0.123). The analysis showed that more acute TBE cases are recorded after a warmer winter and a negative correlation between the abundance of forest Apodemus sp. and the number of TBE cases in the same year.
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Affiliation(s)
- Josip Bago
- Public Health Institute of Varaždin County, 42000 Varaždin, Croatia;
| | - Linda Bjedov
- Faculty of Forestry and Wood Technology, University of Zagreb, 10000 Zagreb, Croatia; (L.B.); (M.V.); (K.T.); (J.M.)
| | - Marko Vucelja
- Faculty of Forestry and Wood Technology, University of Zagreb, 10000 Zagreb, Croatia; (L.B.); (M.V.); (K.T.); (J.M.)
| | - Kristijan Tomljanović
- Faculty of Forestry and Wood Technology, University of Zagreb, 10000 Zagreb, Croatia; (L.B.); (M.V.); (K.T.); (J.M.)
| | - Nataša Cetinić Balent
- University Hospital for Infectious Diseases “Dr. Fran Mihaljević”, 10000 Zagreb, Croatia; (N.C.B.); (S.Z.)
| | - Sanja Zember
- University Hospital for Infectious Diseases “Dr. Fran Mihaljević”, 10000 Zagreb, Croatia; (N.C.B.); (S.Z.)
| | - Josip Margaletić
- Faculty of Forestry and Wood Technology, University of Zagreb, 10000 Zagreb, Croatia; (L.B.); (M.V.); (K.T.); (J.M.)
| | - Oktavija Đaković Rode
- University Hospital for Infectious Diseases “Dr. Fran Mihaljević”, 10000 Zagreb, Croatia; (N.C.B.); (S.Z.)
- School of Dental Medicine, University of Zagreb, 10000 Zagreb, Croatia
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3
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Gervais A, Bastard P, Bizien L, Delifer C, Tiberghien P, Rodrigo C, Trespidi F, Angelini M, Rossini G, Lazzarotto T, Conti F, Cassaniti I, Baldanti F, Rovida F, Ferrari A, Mileto D, Mancon A, Abel L, Puel A, Cobat A, Rice CM, Cadar D, Schmidt-Chanasit J, Scheid JF, Lemieux JE, Rosenberg ES, Agudelo M, Tangye SG, Borghesi A, Durand GA, Duburcq-Gury E, Valencia BM, Lloyd AR, Nagy A, MacDonald MM, Simonin Y, Zhang SY, Casanova JL. Auto-Abs neutralizing type I IFNs in patients with severe Powassan, Usutu, or Ross River virus disease. J Exp Med 2024; 221:e20240942. [PMID: 39485284 PMCID: PMC11533500 DOI: 10.1084/jem.20240942] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 09/11/2024] [Accepted: 09/27/2024] [Indexed: 11/03/2024] Open
Abstract
Arboviral diseases are a growing global health concern. Pre-existing autoantibodies (auto-Abs) neutralizing type I interferons (IFNs) can underlie encephalitis due to West Nile virus (WNV) (∼40% of patients) and tick-borne encephalitis (TBE, due to TBE virus [TBEV]) (∼10%). We report here that these auto-Abs can also underlie severe forms of rarer arboviral infections. Auto-Abs neutralizing high concentrations of IFN-α2, IFN-β, and/or IFN-ω are present in the single case of severe Powassan virus (POWV) encephalitis studied, two of three cases of severe Usutu virus (USUV) infection studied, and the most severe of 24 cases of Ross River virus (RRV) disease studied. These auto-Abs are not found in any of the 137 individuals with silent or mild infections with these three viruses. Thus, auto-Abs neutralizing type I IFNs underlie an increasing list of severe arboviral diseases due to Flaviviridae (WNV, TBEV, POWV, USUV) or Togaviridae (RRV) viruses transmitted to humans by mosquitos (WNV, USUV, RRV) or ticks (TBEV, POWV).
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Affiliation(s)
- Adrian Gervais
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Necker Hospital for Sick Children, Paris, France
- Imagine Institute, Paris Cité University, Paris, France
| | - Paul Bastard
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Necker Hospital for Sick Children, Paris, France
- Imagine Institute, Paris Cité University, Paris, France
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
- Pediatric Hematology-Immunology and Rheumatology Unit, Necker Hospital for Sick Children, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
| | - Lucy Bizien
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Necker Hospital for Sick Children, Paris, France
- Imagine Institute, Paris Cité University, Paris, France
| | - Céline Delifer
- Établissement Français du Sang, La Plaine Saint-Denis, France
| | | | - Chaturaka Rodrigo
- Faculty of Medicine, School of Biomedical Sciences, UNSW Australia, Sydney, Australia
| | - Francesca Trespidi
- Neonatal Intensive Care Unit, San Matteo Research Hospital, Pavia, Italy
| | - Micol Angelini
- Neonatal Intensive Care Unit, San Matteo Research Hospital, Pavia, Italy
| | - Giada Rossini
- Microbiology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Tiziana Lazzarotto
- Microbiology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, Section of Microbiology, University of Bologna, Bologna, Italy
| | - Francesca Conti
- Pediatric Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy
| | - Irene Cassaniti
- Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy
- Microbiology and Virology Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Fausto Baldanti
- Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy
- Microbiology and Virology Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Francesca Rovida
- Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy
- Microbiology and Virology Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Alessandro Ferrari
- Microbiology and Virology Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Davide Mileto
- Laboratory of Clinical Microbiology, Virology and Bioemergencies, Luigi Sacco Hospital, ASST Fatebenefratelli Sacco, Milan, Italy
| | - Alessandro Mancon
- Laboratory of Clinical Microbiology, Virology and Bioemergencies, Luigi Sacco Hospital, ASST Fatebenefratelli Sacco, Milan, Italy
| | - Laurent Abel
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Necker Hospital for Sick Children, Paris, France
- Imagine Institute, Paris Cité University, Paris, France
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
| | - Anne Puel
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Necker Hospital for Sick Children, Paris, France
- Imagine Institute, Paris Cité University, Paris, France
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
| | - Aurélie Cobat
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Necker Hospital for Sick Children, Paris, France
- Imagine Institute, Paris Cité University, Paris, France
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
| | - Charles M. Rice
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA
| | - Dániel Cadar
- Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
| | - Jonas Schmidt-Chanasit
- Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
- Faculty of Mathematics, Informatics and Natural Sciences, University of Hamburg, Hamburg, Germany
| | - Johannes F. Scheid
- Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Jacob E. Lemieux
- Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Eric S. Rosenberg
- Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Marianna Agudelo
- Laboratory of Molecular Immunology, The Rockefeller University, New York, NY, USA
| | - Stuart G. Tangye
- Garvan Institute of Medical Research, Darlinghurst, Australia
- Faculty of Medicine and Health, School of Clinical Medicine, University of New South Wales Sydney, Sydney, Australia
| | - Alessandro Borghesi
- Neonatal Intensive Care Unit, San Matteo Research Hospital, Pavia, Italy
- School of Life Sciences, Swiss Federal Institute of Technology, Lausanne, Switzerland
| | - Guillaume André Durand
- National Reference Center for Arboviruses, Inserm-IRBA, Marseille, France
- Unité des Virus Émergents (UVE: Aix-Marseille Univ-Corsica Univ-IRD 190-Inserm 1207-IRBA), Marseille, France
| | - Emilie Duburcq-Gury
- Intensive Care Unit, Saint Philibert Hospital, Lille Catholic Hospitals, Lille, France
| | | | | | - Anna Nagy
- National Reference Laboratory for Viral Zoonoses, National Public Health Center, Budapest, Hungary
| | - Margaret M. MacDonald
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA
| | - Yannick Simonin
- Pathogenesis and Control of Chronic and Emerging Infections, University of Montpellier, INSERM, EFS, Montpellier, France
| | - Shen-Ying Zhang
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Necker Hospital for Sick Children, Paris, France
- Imagine Institute, Paris Cité University, Paris, France
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
| | - Jean-Laurent Casanova
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Necker Hospital for Sick Children, Paris, France
- Imagine Institute, Paris Cité University, Paris, France
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
- Howard Hughes Medical Institute, New York, NY, USA
- Department of Pediatrics, Necker Hospital for Sick Children, AP-HP, Paris, France
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4
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Gasmi S, Ogden NH, Bourgeois AC, Mitri ME, Buck P, Koffi JK. Incidence of hospitalizations related to Lyme disease and other tick-borne diseases using Discharge Abstract Database, Canada, 2009-2021. PLoS One 2024; 19:e0312703. [PMID: 39453942 PMCID: PMC11508055 DOI: 10.1371/journal.pone.0312703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Accepted: 10/11/2024] [Indexed: 10/27/2024] Open
Abstract
To estimate rates of hospitalizations for tick-borne diseases (TBDs) in Canada, retrospective analysis was conducted to determine the incidence of patients diagnosed with TBDs during their hospital stay in Canada, and describe demographic characteristics, temporal trends and geographic distributions, from 2009 through 2021. Codes from the International Classification of Diseases, Tenth Revision (ICD-10-CA) were used to capture diagnoses of TBDs in the Discharge Abstract Database (DAD) in Canadian hospitals. From 2009 through 2021, 1,626 patients were diagnosed with TBDs during their hospital stay. Of these, 1,457 were diagnosed with Lyme disease (LD), 162 with other TBDs, and seven were diagnosed with more than one TBD. Annual hospitalization counts for LD showed a significant increase from 50 in 2009 to 259 in 2021 (incidence rate per 100,000 population of 0.1 and 0.7, respectively). Epidemiologic patterns for hospitalized LD cases, including increases and variation in annual incidences, seasonality, demographics and geographic distribution, are consistent with those elucidated in national LD surveillance data. Amongst 162 patients diagnosed with other tick-borne diseases, discharge diagnoses were: rickettsiosis (32.7%), spotted fever due to rickettsia rickettsii (23.5%), tularemia (21.0%), babesiosis (8.6%), other tick-borne viral encephalitis (6.2%), tick-borne relapsing fever (4.9%), and Colorado tick fever (0.6%). Annual incidence increased only for rickettsiosis from 3 to 12 patients over the study period. Monitoring the data of hospitalizations using the DAD provided insights into the burden of emerging TBDs, the severity of illnesses and the population most at risk.
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Affiliation(s)
- Salima Gasmi
- Centre for Food-borne, Environmental and Zoonotic Infectious Diseases, Public Health Agency of Canada, Saint-Hyacinthe, Québec, Canada
- Groupe de Recherche en Épidémiologie des Zoonoses et Santé Publique, Université de Montréal, St-Hyacinthe, Québec, Canada
| | - Nicholas H. Ogden
- Groupe de Recherche en Épidémiologie des Zoonoses et Santé Publique, Université de Montréal, St-Hyacinthe, Québec, Canada
- Public Health Risk Sciences Division, Scientific Operations and Response, National Microbiology Laboratory, Public Health Agency of Canada, Saint-Hyacinthe, Québec, Canada
- Centre de Recherche en Santé Publique, Université de Montréal, Montréal, Québec, Canada
| | - Annie-Claude Bourgeois
- Centre for Food-borne, Environmental and Zoonotic Infectious Diseases, Public Health Agency of Canada, Ottawa, Ontario, Canada
| | - Maria Elizabeth Mitri
- Centre for Food-borne, Environmental and Zoonotic Infectious Diseases, Public Health Agency of Canada, Ottawa, Ontario, Canada
| | - Peter Buck
- Centre for Food-borne, Environmental and Zoonotic Infectious Diseases, Public Health Agency of Canada, Ottawa, Ontario, Canada
| | - Jules K. Koffi
- Centre for Food-borne, Environmental and Zoonotic Infectious Diseases, Public Health Agency of Canada, Saint-Hyacinthe, Québec, Canada
- Groupe de Recherche en Épidémiologie des Zoonoses et Santé Publique, Université de Montréal, St-Hyacinthe, Québec, Canada
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Gervais A, Marchal A, Fortova A, Berankova M, Krbkova L, Pychova M, Salat J, Zhao S, Kerrouche N, Le Voyer T, Stiasny K, Raffl S, Schieber Pachart A, Fafi-Kremer S, Gravier S, Robbiani DF, Abel L, MacDonald MR, Rice CM, Weissmann G, Kamal Eldin T, Robatscher E, Erne EM, Pagani E, Borghesi A, Puel A, Bastard P, Velay A, Martinot M, Hansmann Y, Aberle JH, Ruzek D, Cobat A, Zhang SY, Casanova JL. Autoantibodies neutralizing type I IFNs underlie severe tick-borne encephalitis in ∼10% of patients. J Exp Med 2024; 221:e20240637. [PMID: 39316018 PMCID: PMC11448868 DOI: 10.1084/jem.20240637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 07/10/2024] [Accepted: 08/12/2024] [Indexed: 09/25/2024] Open
Abstract
Tick-borne encephalitis (TBE) virus (TBEV) is transmitted to humans via tick bites. Infection is benign in >90% of the cases but can cause mild (<5%), moderate (<4%), or severe (<1%) encephalitis. We show here that ∼10% of patients hospitalized for severe TBE in cohorts from Austria, Czech Republic, and France carry auto-Abs neutralizing IFN-α2, -β, and/or -ω at the onset of disease, contrasting with only ∼1% of patients with moderate and mild TBE. These auto-Abs were found in two of eight patients who died and none of 13 with silent infection. The odds ratios (OR) for severe TBE in individuals with these auto-Abs relative to those without them in the general population were 4.9 (95% CI: 1.5-15.9, P < 0.0001) for the neutralization of only 100 pg/ml IFN-α2 and/or -ω, and 20.8 (95% CI: 4.5-97.4, P < 0.0001) for the neutralization of 10 ng/ml IFN-α2 and -ω. Auto-Abs neutralizing type I IFNs accounted for ∼10% of severe TBE cases in these three European cohorts.
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Affiliation(s)
- Adrian Gervais
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Necker Hospital for Sick Children, Paris, France
- Imagine Institute, Paris Cité University, Paris, France
| | - Astrid Marchal
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Necker Hospital for Sick Children, Paris, France
- Imagine Institute, Paris Cité University, Paris, France
| | - Andrea Fortova
- Laboratory of Emerging Viral Diseases, Veterinary Research Institute, Brno, Czech Republic
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic
- Institute of Parasitology, Biology Centre of the Czech Academy of Science, České Budějovice, Czech Republic
| | - Michaela Berankova
- Laboratory of Emerging Viral Diseases, Veterinary Research Institute, Brno, Czech Republic
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic
- Institute of Parasitology, Biology Centre of the Czech Academy of Science, České Budějovice, Czech Republic
| | - Lenka Krbkova
- Department of Children’s Infectious Diseases, University Hospital and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Martina Pychova
- Department of Infectious Diseases, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Jiri Salat
- Laboratory of Emerging Viral Diseases, Veterinary Research Institute, Brno, Czech Republic
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic
- Institute of Parasitology, Biology Centre of the Czech Academy of Science, České Budějovice, Czech Republic
| | - Shuxiang Zhao
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
| | - Nacim Kerrouche
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
| | - Tom Le Voyer
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Necker Hospital for Sick Children, Paris, France
- Imagine Institute, Paris Cité University, Paris, France
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
- Clinical Immunology Department, Assistance Publique Hôpitaux de Paris (AP-HP), Saint-Louis Hospital, Paris, France
| | - Karin Stiasny
- Medical University of Vienna, Center for Virology, Vienna, Austria
| | - Simon Raffl
- Medical University of Vienna, Center for Virology, Vienna, Austria
| | | | - Samira Fafi-Kremer
- Institut de Virologie, Strasbourg University Hospital, Strasbourg University, INSERM Unité Mixte de Recherche (UMR) S1109, Strasbourg, France
| | - Simon Gravier
- Infectious Diseases Department, Hôpitaux Civils, Colmar, France
| | - Davide F. Robbiani
- Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona, Switzerland
| | - Laurent Abel
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Necker Hospital for Sick Children, Paris, France
- Imagine Institute, Paris Cité University, Paris, France
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
| | - Margaret R. MacDonald
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA
| | - Charles M. Rice
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA
| | - Gaia Weissmann
- Department of Pediatrics and Neonatology, F. Tappeiner Hospital, Merano, Italy
| | - Tarek Kamal Eldin
- Infectious Disease Unit, Provincial Hospital of Bolzano (SABES-ASDAA), Lehrkrankenhaus der Paracelsus Medizinischen Privatuniversität, Bolzano, Italy
| | - Eva Robatscher
- Laboratory of Microbiology and Virology, SABES-ASDAA, Lehrkrankenhaus der Paracelsus Medizinischen Privatuniversität, Bolzano, Italy
| | - Elke Maria Erne
- Infectious Disease Unit, Provincial Hospital of Bolzano (SABES-ASDAA), Lehrkrankenhaus der Paracelsus Medizinischen Privatuniversität, Bolzano, Italy
| | - Elisabetta Pagani
- Laboratory of Microbiology and Virology, SABES-ASDAA, Lehrkrankenhaus der Paracelsus Medizinischen Privatuniversität, Bolzano, Italy
| | - Alessandro Borghesi
- Neonatal Intensive Care Unit, San Matteo Research Hospital, Pavia, Italy
- School of Life Sciences, Swiss Federal Institute of Technology, Lausanne, Switzerland
| | - Anne Puel
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Necker Hospital for Sick Children, Paris, France
- Imagine Institute, Paris Cité University, Paris, France
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
| | - Paul Bastard
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Necker Hospital for Sick Children, Paris, France
- Imagine Institute, Paris Cité University, Paris, France
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
- Pediatric Hematology-Immunology and Rheumatology Unit, Necker Hospital for Sick Children, AP-HP, Paris, France
| | - Aurélie Velay
- Institut de Virologie, Strasbourg University Hospital, Strasbourg University, INSERM Unité Mixte de Recherche (UMR) S1109, Strasbourg, France
| | - Martin Martinot
- Infectious Diseases Department, Hôpitaux Civils, Colmar, France
| | - Yves Hansmann
- CHU de Strasbourg, Service des Maladies Infectieuses et Tropicales, Strasbourg, France
| | - Judith H. Aberle
- Medical University of Vienna, Center for Virology, Vienna, Austria
| | - Daniel Ruzek
- Laboratory of Emerging Viral Diseases, Veterinary Research Institute, Brno, Czech Republic
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic
- Institute of Parasitology, Biology Centre of the Czech Academy of Science, České Budějovice, Czech Republic
| | - Aurélie Cobat
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Necker Hospital for Sick Children, Paris, France
- Imagine Institute, Paris Cité University, Paris, France
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
| | - Shen-Ying Zhang
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Necker Hospital for Sick Children, Paris, France
- Imagine Institute, Paris Cité University, Paris, France
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
| | - Jean-Laurent Casanova
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Necker Hospital for Sick Children, Paris, France
- Imagine Institute, Paris Cité University, Paris, France
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
- Howard Hughes Medical Institute, New York, NY, USA
- Department of Pediatrics, Necker Hospital for Sick Children, AP-HP, Paris, France
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6
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Cannac M, Nisole S. TRIMming down Flavivirus Infections. Viruses 2024; 16:1262. [PMID: 39205236 PMCID: PMC11359179 DOI: 10.3390/v16081262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 08/02/2024] [Accepted: 08/06/2024] [Indexed: 09/04/2024] Open
Abstract
Flaviviruses comprise a large number of arthropod-borne viruses, some of which are associated with life-threatening diseases. Flavivirus infections are rising worldwide, mainly due to the proliferation and geographical expansion of their vectors. The main human pathogens are mosquito-borne flaviviruses, including dengue virus, Zika virus, and West Nile virus, but tick-borne flaviviruses are also emerging. As with any viral infection, the body's first line of defense against flavivirus infections is the innate immune defense, of which type I interferon is the armed wing. This cytokine exerts its antiviral activity by triggering the synthesis of hundreds of interferon-induced genes (ISGs), whose products can prevent infection. Among the ISGs that inhibit flavivirus replication, certain tripartite motif (TRIM) proteins have been identified. Although involved in other biological processes, TRIMs constitute a large family of antiviral proteins active on a wide range of viruses. Furthermore, whereas some TRIM proteins directly block viral replication, others are positive regulators of the IFN response. Therefore, viruses have developed strategies to evade or counteract TRIM proteins, and some even hijack certain TRIM proteins to their advantage. In this review, we summarize the current state of knowledge on the interactions between flaviviruses and TRIM proteins, covering both direct and indirect antiviral mechanisms.
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Affiliation(s)
| | - Sébastien Nisole
- Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier, CNRS, 34090 Montpellier, France
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7
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Wang LL, Cheng Q, Newton ND, Wolfinger MT, Morgan MS, Slonchak A, Khromykh AA, Cheng TY, Parry RH. Xinyang flavivirus, from Haemaphysalis flava ticks in Henan Province, China, defines a basal, likely tick-only Orthoflavivirus clade. J Gen Virol 2024; 105:001991. [PMID: 38809251 PMCID: PMC11165663 DOI: 10.1099/jgv.0.001991] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Accepted: 05/08/2024] [Indexed: 05/30/2024] Open
Abstract
Tick-borne orthoflaviviruses (TBFs) are classified into three conventional groups based on genetics and ecology: mammalian, seabird and probable-TBF group. Recently, a fourth basal group has been identified in Rhipicephalus ticks from Africa: Mpulungu flavivirus (MPFV) in Zambia and Ngoye virus (NGOV) in Senegal. Despite attempts, isolating these viruses in vertebrate and invertebrate cell lines or intracerebral injection of newborn mice with virus-containing homogenates has remained unsuccessful. In this study, we report the discovery of Xinyang flavivirus (XiFV) in Haemaphysalis flava ticks from Xìnyáng, Henan Province, China. Phylogenetic analysis shows that XiFV was most closely related to MPFV and NGOV, marking the first identification of this tick orthoflavivirus group in Asia. We developed a reverse transcriptase quantitative PCR assay to screen wild-collected ticks and egg clutches, with absolute infection rates of 20.75 % in adult females and 15.19 % in egg clutches, suggesting that XiFV could be potentially spread through transovarial transmission. To examine potential host range, dinucleotide composition analyses revealed that XiFV, MPFV and NGOV share a closer composition to classical insect-specific orthoflaviviruses than to vertebrate-infecting TBFs, suggesting that XiFV could be a tick-only orthoflavivirus. Additionally, both XiFV and MPFV lack a furin cleavage site in the prM protein, unlike other TBFs, suggesting these viruses might exist towards a biased immature particle state. To examine this, chimeric Binjari virus with XIFV-prME (bXiFV) was generated, purified and analysed by SDS-PAGE and negative-stain transmission electron microscopy, suggesting prototypical orthoflavivirus size (~50 nm) and bias towards uncleaved prM. In silico structural analyses of the 3'-untranslated regions show that XiFV forms up to five pseudo-knot-containing stem-loops and a prototypical orthoflavivirus dumbbell element, suggesting the potential for multiple exoribonuclease-resistant RNA structures.
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Affiliation(s)
- Lan-Lan Wang
- College of Veterinary Medicine, Hunan Agricultural University, Changsha, Hunan Province, PR China
| | - Qia Cheng
- Children’s Medical Center, Hunan Provincial People’s Hospital, Changsha, PR China
| | - Natalee D. Newton
- School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD, Australia
- Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD, Australia
| | - Michael T. Wolfinger
- Department of Theoretical Chemistry, University of Vienna, Vienna, Austria
- Research Group Bioinformatics and Computational Biology, Faculty of Computer Science, University of Vienna, Vienna, Austria
- Bioinformatics Group, Department of Computer Science, University of Freiburg, Freiburg, Germany
- RNA Forecast e.U., Vienna, Austria
| | - Mahali S. Morgan
- School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD, Australia
| | - Andrii Slonchak
- School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD, Australia
- Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD, Australia
| | - Alexander A. Khromykh
- School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD, Australia
- Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD, Australia
- GVN Center of Excellence, Australian Infectious Diseases Research Centre, Brisbane, QLD, Australia
| | - Tian-Yin Cheng
- College of Veterinary Medicine, Hunan Agricultural University, Changsha, Hunan Province, PR China
| | - Rhys H. Parry
- School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD, Australia
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8
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Brisse M, Ly H. Langat virus, a prototypic tick-borne encephalitis virus, impacts IL-6 signaling by downregulating gp130 expression. J Med Virol 2024; 96:e29572. [PMID: 38533946 DOI: 10.1002/jmv.29572] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 03/16/2024] [Accepted: 03/18/2024] [Indexed: 03/28/2024]
Affiliation(s)
- Morgan Brisse
- Viral Immunity and Pathogenesis Unit, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA
| | - Hinh Ly
- Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, Minnesota, USA
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9
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Lin S, Wang X, Sallapalli BT, Hage A, Chang P, He J, Best SM, Zhang Y. Langat virus inhibits the gp130/JAK/STAT signaling by reducing the gp130 protein level. J Med Virol 2024; 96:e29522. [PMID: 38533889 DOI: 10.1002/jmv.29522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 02/08/2024] [Accepted: 02/29/2024] [Indexed: 03/28/2024]
Abstract
The tick-borne encephalitis virus (TBEV) serocomplex includes several medically important flavivirus members endemic to Europe, Asia, and North America, which can induce severe neuroinvasive or viscerotropic diseases with unclear mechanisms of pathogenesis. Langat virus (LGTV) shares a high sequence identity with TBEV but exhibits lower pathogenic potential in humans and serves as a model for virus-host interactions. In this study, we demonstrated that LGTV infection inhibits the activation of gp130/JAK/STAT (Janus kinases (JAK) and signal transducer and activator of transcription (STAT)) signaling, which plays a pivotal role in numerous biological processes. Our data show that the LGTV-infected cells had significantly lower phosphorylated STAT3 (pSTAT3) protein upon oncostatin M (OSM) stimulation than the mock-infected control. LGTV infection blocked the nuclear translocation of STAT3 without a significant effect on total STAT3 protein level. LGTV inhibited JAK1 activation and reduced gp130 protein expression in infected cells, with the viral NS5 protein mediating this effect. TBEV infection also reduces gp130 level. On the other hand, pretreatment of Vero cells with OSM significantly reduces LGTV replication, and STAT1/STAT2 knockdown had little effect on OSM-mediated antiviral effect, which suggests it is independent of STAT1/STAT2 and, instead, it is potentially mediated by STAT3 signlaing. These findings shed light on the LGTV and TBEV-cell interactions, offering insights for the future development of antiviral therapeutics and improved vaccines.
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Affiliation(s)
- Shaoli Lin
- Molecular Virology Laboratory, Virginia-Maryland College of Veterinary Medicine, University of Maryland, College Park, MD, USA
| | - Xiaochun Wang
- Molecular Virology Laboratory, Virginia-Maryland College of Veterinary Medicine, University of Maryland, College Park, MD, USA
| | - Bhargava Teja Sallapalli
- Molecular Virology Laboratory, Virginia-Maryland College of Veterinary Medicine, University of Maryland, College Park, MD, USA
| | - Adam Hage
- Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, USA
| | - Peixi Chang
- Molecular Virology Laboratory, Virginia-Maryland College of Veterinary Medicine, University of Maryland, College Park, MD, USA
| | - Jia He
- Molecular Virology Laboratory, Virginia-Maryland College of Veterinary Medicine, University of Maryland, College Park, MD, USA
| | - Sonja M Best
- Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, USA
| | - Yanjin Zhang
- Molecular Virology Laboratory, Virginia-Maryland College of Veterinary Medicine, University of Maryland, College Park, MD, USA
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10
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Kubinski M, Beicht J, Gerlach T, Aregay A, Osterhaus ADME, Tscherne A, Sutter G, Prajeeth CK, Rimmelzwaan GF. Immunity to Tick-Borne Encephalitis Virus NS3 Protein Induced with a Recombinant Modified Vaccinia Virus Ankara Fails to Afford Mice Protection against TBEV Infection. Vaccines (Basel) 2024; 12:105. [PMID: 38276677 PMCID: PMC10819467 DOI: 10.3390/vaccines12010105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 01/16/2024] [Accepted: 01/17/2024] [Indexed: 01/27/2024] Open
Abstract
Tick-borne encephalitis (TBE) is a serious neurological disease caused by TBE virus (TBEV). Because antiviral treatment options are not available, vaccination is the key prophylactic measure against TBEV infections. Despite the availability of effective vaccines, cases of vaccination breakthrough infections have been reported. The multienzymatic non-structural protein 3 (NS3) of orthoflaviviruses plays an important role in polyprotein processing and virus replication. In the present study, we evaluated NS3 of TBEV as a potential vaccine target for the induction of protective immunity. To this end, a recombinant modified vaccinia virus Ankara that drives the expression of the TBEV NS3 gene (MVA-NS3) was constructed. MVA-NS3 was used to immunize C57BL/6 mice. It induced NS3-specific immune responses, in particular T cell responses, especially against the helicase domain of NS3. However, MVA-NS3-immunized mice were not protected from subsequent challenge infection with a lethal dose of the TBEV strain Neudoerfl, indicating that in contrast to immunity to prME and NS1, NS3-specific immunity is not an independent correlate of protection against TBEV in this mouse model.
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Affiliation(s)
- Mareike Kubinski
- Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, Foundation, Bünteweg 17, 30559 Hannover, Germany; (M.K.); (J.B.); (T.G.); (A.A.); (A.D.M.E.O.); (C.K.P.)
| | - Jana Beicht
- Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, Foundation, Bünteweg 17, 30559 Hannover, Germany; (M.K.); (J.B.); (T.G.); (A.A.); (A.D.M.E.O.); (C.K.P.)
| | - Thomas Gerlach
- Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, Foundation, Bünteweg 17, 30559 Hannover, Germany; (M.K.); (J.B.); (T.G.); (A.A.); (A.D.M.E.O.); (C.K.P.)
| | - Amare Aregay
- Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, Foundation, Bünteweg 17, 30559 Hannover, Germany; (M.K.); (J.B.); (T.G.); (A.A.); (A.D.M.E.O.); (C.K.P.)
| | - Albert D. M. E. Osterhaus
- Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, Foundation, Bünteweg 17, 30559 Hannover, Germany; (M.K.); (J.B.); (T.G.); (A.A.); (A.D.M.E.O.); (C.K.P.)
| | - Alina Tscherne
- Division of Virology, Institute for Infectious Diseases and Zoonoses, Ludwig Maximilian University Munich, Sonnenstraße 24, 85764 Oberschleißheim, Germany; (A.T.)
- German Center for Infection Research (DZIF), Partner Site Munich, 80802 Munich, Germany
| | - Gerd Sutter
- Division of Virology, Institute for Infectious Diseases and Zoonoses, Ludwig Maximilian University Munich, Sonnenstraße 24, 85764 Oberschleißheim, Germany; (A.T.)
- German Center for Infection Research (DZIF), Partner Site Munich, 80802 Munich, Germany
| | - Chittappen Kandiyil Prajeeth
- Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, Foundation, Bünteweg 17, 30559 Hannover, Germany; (M.K.); (J.B.); (T.G.); (A.A.); (A.D.M.E.O.); (C.K.P.)
| | - Guus F. Rimmelzwaan
- Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, Foundation, Bünteweg 17, 30559 Hannover, Germany; (M.K.); (J.B.); (T.G.); (A.A.); (A.D.M.E.O.); (C.K.P.)
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11
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Camarão AAR, Gern OL, Stegmann F, Mulenge F, Costa B, Saremi B, Jung K, Lepenies B, Kalinke U, Steffen I. Secreted NS1 proteins of tick-borne encephalitis virus and West Nile virus block dendritic cell activation and effector functions. Microbiol Spectr 2023; 11:e0219223. [PMID: 37707204 PMCID: PMC10581055 DOI: 10.1128/spectrum.02192-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Accepted: 07/13/2023] [Indexed: 09/15/2023] Open
Abstract
The flavivirus non-structural protein 1 (NS1) is secreted from infected cells into the circulation and the serum levels correlate with disease severity. The effect of secreted NS1 (sNS1) on non-infected mammalian immune cells is largely unknown. Here, we expressed recombinant sNS1 proteins of tick-borne encephalitis virus (TBEV) and West Nile virus (WNV) and investigated their effects on dendritic cell (DC) effector functions. Murine bone marrow-derived DCs (BMDCs) showed reduced surface expression of co-stimulatory molecules and decreased release of pro-inflammatory cytokines when treated with sNS1 of TBEV or WNV prior to poly(I:C) stimulation. Transcriptional profiles of BMDCs that were sNS1-exposed prior to poly(I:C) stimulation showed two gene clusters that were downregulated by TBEV or WNV sNS1 and that were associated with innate and adaptive immune responses. Functionally, both sNS1 proteins modulated the capacity for BMDCs to induce specific T-cell responses as indicated by reduced IFN-γ levels in both CD4+ and CD8+ T cells after BMDC co-cultivation. In human monocyte-derived DCs, poly(I:C)-induced upregulation of co-stimulatory molecules and cytokine responses were even more strongly impaired by TBEV sNS1 or WNV sNS1 pretreatment than in the murine system. Our findings indicate that exogenous flaviviral sNS1 proteins interfere with DC-mediated stimulation of T cells, which is crucial for the initiation of cell-mediated adaptive immune responses in human flavivirus infections. Collectively, our data determine soluble flaviviral NS1 as a virulence factor responsible for a dampened immune response to flavivirus infections. IMPORTANCE The effective initiation of protective host immune responses controls the outcome of infection, and dysfunctional T-cell responses have previously been associated with symptomatic human flavivirus infections. We demonstrate that secreted flavivirus NS1 proteins modulate innate immune responses of uninfected bystander cells. In particular, sNS1 markedly reduced the capacity of dendritic cells to stimulate T-cell responses upon activation. Hence, by modulating cellular host responses that are required for effective antigen presentation and initiation of adaptive immunity, sNS1 proteins may contribute to severe outcomes of flavivirus disease.
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Affiliation(s)
- António A. R. Camarão
- Institute of Biochemistry, University of Veterinary Medicine Hannover, Hannover, Germany
- Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, Hannover, Germany
| | - Olivia Luise Gern
- Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, Hannover, Germany
| | - Felix Stegmann
- Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, Hannover, Germany
- Institute for Immunology, University of Veterinary Medicine Hannover, Hannover, Germany
| | - Felix Mulenge
- Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, Hannover, Germany
| | - Bibiana Costa
- Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, Hannover, Germany
| | - Babak Saremi
- Institute for Animal Breeding and Genetics, University of Veterinary Medicine Hannover, Hannover, Germany
| | - Klaus Jung
- Institute for Animal Breeding and Genetics, University of Veterinary Medicine Hannover, Hannover, Germany
| | - Bernd Lepenies
- Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, Hannover, Germany
- Institute for Immunology, University of Veterinary Medicine Hannover, Hannover, Germany
| | - Ulrich Kalinke
- Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, Hannover, Germany
- Cluster of Excellence—Resolving Infection Susceptibility (RESIST, EXC 2155), Hannover Medical School, Hannover, Germany
| | - Imke Steffen
- Institute of Biochemistry, University of Veterinary Medicine Hannover, Hannover, Germany
- Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, Hannover, Germany
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12
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Chiffi G, Grandgirard D, Leib SL, Chrdle A, Růžek D. Tick-borne encephalitis: A comprehensive review of the epidemiology, virology, and clinical picture. Rev Med Virol 2023; 33:e2470. [PMID: 37392370 DOI: 10.1002/rmv.2470] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 05/31/2023] [Accepted: 06/12/2023] [Indexed: 07/03/2023]
Abstract
Tick-borne encephalitis virus (TBEV) is a flavivirus commonly found in at least 27 European and Asian countries. It is an emerging public health problem, with steadily increasing case numbers over recent decades. Tick-borne encephalitis virus affects between 10,000 and 15,000 patients annually. Infection occurs through the bite of an infected tick and, much less commonly, through infected milk consumption or aerosols. The TBEV genome comprises a positive-sense single-stranded RNA molecule of ∼11 kilobases. The open reading frame is > 10,000 bases long, flanked by untranslated regions (UTR), and encodes a polyprotein that is co- and post-transcriptionally processed into three structural and seven non-structural proteins. Tick-borne encephalitis virus infection results in encephalitis, often with a characteristic biphasic disease course. After a short incubation time, the viraemic phase is characterised by non-specific influenza-like symptoms. After an asymptomatic period of 2-7 days, more than half of patients show progression to a neurological phase, usually characterised by central and, rarely, peripheral nervous system symptoms. Mortality is low-around 1% of confirmed cases, depending on the viral subtype. After acute tick-borne encephalitis (TBE), a minority of patients experience long-term neurological deficits. Additionally, 40%-50% of patients develop a post-encephalitic syndrome, which significantly impairs daily activities and quality of life. Although TBEV has been described for several decades, no specific treatment exists. Much remains unknown regarding the objective assessment of long-lasting sequelae. Additional research is needed to better understand, prevent, and treat TBE. In this review, we aim to provide a comprehensive overview of the epidemiology, virology, and clinical picture of TBE.
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Affiliation(s)
- Gabriele Chiffi
- Department for BioMedical Research, University of Bern, Bern, Switzerland
- Institute for Infectious Diseases, University of Bern, Bern, Switzerland
| | - Denis Grandgirard
- Institute for Infectious Diseases, University of Bern, Bern, Switzerland
| | - Stephen L Leib
- Institute for Infectious Diseases, University of Bern, Bern, Switzerland
| | - Aleš Chrdle
- Department of Infectious Diseases, Hospital Ceske Budejovice, Ceske Budejovice, Czech Republic
- Faculty of Health and Social Sciences, University of South Bohemia, Ceske Budejovice, Czech Republic
- Royal Liverpool University Hospital, Liverpool, UK
| | - Daniel Růžek
- Veterinary Research Institute, Emerging Viral Diseases, Brno, Czech Republic
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic
- Institute of Parasitology, Biology Centre of the Czech Academy of Sciences, Ceske Budejovice, Czech Republic
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13
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Kjær LJ, Johansson M, Lindgren PE, Asghar N, Wilhelmsson P, Fredlund H, Christensson M, Wallenhammar A, Bødker R, Rasmussen G, Kjellander P. Potential drivers of human tick-borne encephalitis in the Örebro region of Sweden, 2010-2021. Sci Rep 2023; 13:7685. [PMID: 37169798 PMCID: PMC10175290 DOI: 10.1038/s41598-023-34675-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Accepted: 05/05/2023] [Indexed: 05/13/2023] Open
Abstract
Incidence of tick-borne encephalitis (TBE) has increased during the last years in Scandinavia, but the underlying mechanism is not understood. TBE human case data reported between 2010 and 2021 were aggregated into postal codes within Örebro County, south-central Sweden, along with tick abundance and environmental data to analyse spatial patterns and identify drivers of TBE. We identified a substantial and continuing increase of TBE incidence in Örebro County during the study period. Spatial cluster analyses showed significant hotspots (higher number of cases than expected) in the southern and northern parts of Örebro County, whereas a cold spot (lower number of cases than expected) was found in the central part comprising Örebro municipality. Generalised linear models showed that the risk of acquiring TBE increased by 12.5% and 72.3% for every percent increase in relative humidity and proportion of wetland forest, respectively, whereas the risk decreased by 52.8% for every degree Celsius increase in annual temperature range. However, models had relatively low goodness of fit (R2 < 0.27). Results suggest that TBE in Örebro County is spatially clustered, however variables used in this study, i.e., climatic variables, forest cover, water, tick abundance, sheep as indicator species, alone do not explain this pattern.
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Affiliation(s)
- Lene Jung Kjær
- Section for Animal Welfare and Disease Control, Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark.
| | - Magnus Johansson
- School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Per-Eric Lindgren
- Division of Inflammation and Infection, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
- Division of Clinical Microbiology, Department of Laboratory Medicine, Region Jönköping County, Jönköping, Sweden
| | - Naveed Asghar
- School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Peter Wilhelmsson
- Division of Inflammation and Infection, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
- Division of Clinical Microbiology, Department of Laboratory Medicine, Region Jönköping County, Jönköping, Sweden
| | - Hans Fredlund
- Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
- Örebro County Council, Örebro, Sweden
| | - Madeleine Christensson
- Grimsö Wildlife Research Station, Department of Ecology, Swedish University of Agricultural Sciences (SLU), Riddarhyttan, Sweden
| | - Amélie Wallenhammar
- School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - René Bødker
- Section for Animal Welfare and Disease Control, Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark
| | - Gunløg Rasmussen
- School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
- Örebro County Council, Örebro, Sweden
| | - Petter Kjellander
- Grimsö Wildlife Research Station, Department of Ecology, Swedish University of Agricultural Sciences (SLU), Riddarhyttan, Sweden
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14
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Gothe LMR, Ganzenberg S, Ziegler U, Obiegala A, Lohmann KL, Sieg M, Vahlenkamp TW, Groschup MH, Hörügel U, Pfeffer M. Horses as Sentinels for the Circulation of Flaviviruses in Eastern-Central Germany. Viruses 2023; 15:v15051108. [PMID: 37243194 DOI: 10.3390/v15051108] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 04/27/2023] [Accepted: 04/28/2023] [Indexed: 05/28/2023] Open
Abstract
Since 2018, autochthonous West Nile virus (WNV) infections have been regularly reported in eastern-central Germany. While clinically apparent infections in humans and horses are not frequent, seroprevalence studies in horses may allow the tracing of WNV and related flaviviruses transmission, such as tick-borne encephalitis virus (TBEV) and Usutu virus (USUV), and consequently help to estimate the risk of human infections. Hence, the aim of our study was to follow the seropositive ratio against these three viruses in horses in Saxony, Saxony Anhalt, and Brandenburg and to describe their geographic distribution for the year 2021. In early 2022, i.e., before the virus transmission season, sera from 1232 unvaccinated horses were tested using a competitive pan-flavivirus ELISA (cELISA). In order to estimate the true seropositive ratio of infection with WNV, TBEV, and USUV for 2021, positive and equivocal results were confirmed by a virus neutralization test (VNT). In addition, possible risk factors for seropositivity using questionnaires were analyzed using logistic regression based on questionnaires similar to our previous study from 2020. In total, 125 horse sera reacted positive in the cELISA. Based on the VNT, 40 sera showed neutralizing antibodies against WNV, 69 against TBEV, and 5 against USUV. Three sera showed antibodies against more than one virus, and eight were negative based on the VNT. The overall seropositive ratio was 3.3% (95% CI: 2.38-4.40) for WNV, 5.6% (95% CI: 4.44-7.04) for TBEV, and 0.4% (95% CI: 0.14-0.98) for USUV infections. While age and number of horses on the holding were factors predicting TBEV seropositivity, no risk factors were discovered for WNV seropositivity. We conclude that horses are useful sentinels to determine the flavivirus circulation in eastern-central Germany, as long as they are not vaccinated against WNV.
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Affiliation(s)
- Leonard M R Gothe
- Institute of Animal Hygiene and Veterinary Public Health, Faculty of Veterinary Medicine, Leipzig University, 04103 Leipzig, Germany
| | - Stefanie Ganzenberg
- Department for Horses, Faculty of Veterinary Medicine, Leipzig University, 04103 Leipzig, Germany
| | - Ute Ziegler
- Friedrich-Loeffler Institut (FLI), Federal Research Institute for Animal Health, Institute of Novel and Emerging Infectious Diseases, 17493 Greifswald-Insel Riems, Germany
| | - Anna Obiegala
- Institute of Animal Hygiene and Veterinary Public Health, Faculty of Veterinary Medicine, Leipzig University, 04103 Leipzig, Germany
| | - Katharina L Lohmann
- Department for Horses, Faculty of Veterinary Medicine, Leipzig University, 04103 Leipzig, Germany
| | - Michael Sieg
- Institute of Virology, Faculty of Veterinary Medicine, Leipzig University, 04103 Leipzig, Germany
| | - Thomas W Vahlenkamp
- Institute of Virology, Faculty of Veterinary Medicine, Leipzig University, 04103 Leipzig, Germany
| | - Martin H Groschup
- Friedrich-Loeffler Institut (FLI), Federal Research Institute for Animal Health, Institute of Novel and Emerging Infectious Diseases, 17493 Greifswald-Insel Riems, Germany
| | - Uwe Hörügel
- Animal Diseases Fund Saxony, Horse Health Service, 01099 Dresden, Germany
| | - Martin Pfeffer
- Institute of Animal Hygiene and Veterinary Public Health, Faculty of Veterinary Medicine, Leipzig University, 04103 Leipzig, Germany
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15
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Kubinski M, Beicht J, Zdora I, Biermann J, Puff C, Gerlach T, Tscherne A, Baumgärtner W, Osterhaus ADME, Sutter G, Prajeeth CK, Rimmelzwaan GF. A recombinant Modified Vaccinia virus Ankara expressing prME of tick-borne encephalitis virus affords mice full protection against TBEV infection. Front Immunol 2023; 14:1182963. [PMID: 37153588 PMCID: PMC10160477 DOI: 10.3389/fimmu.2023.1182963] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Accepted: 03/30/2023] [Indexed: 05/09/2023] Open
Abstract
Introduction Tick-borne encephalitis virus (TBEV) is an important human pathogen that can cause a serious disease involving the central nervous system (tick-borne encephalitis, TBE). Although approved inactivated vaccines are available, the number of TBE cases is rising, and breakthrough infections in fully vaccinated subjects have been reported in recent years. Methods In the present study, we generated and characterized a recombinant Modified Vaccinia virus Ankara (MVA) for the delivery of the pre-membrane (prM) and envelope (E) proteins of TBEV (MVA-prME). Results MVA-prME was tested in mice in comparison with a licensed vaccine FSME-IMMUN® and proved to be highly immunogenic and afforded full protection against challenge infection with TBEV. Discussion Our data indicate that MVA-prME holds promise as an improved next-generation vaccine for the prevention of TBE.
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Affiliation(s)
- Mareike Kubinski
- Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, Foundation, Hannover, Germany
| | - Jana Beicht
- Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, Foundation, Hannover, Germany
| | - Isabel Zdora
- Department of Pathology, University of Veterinary Medicine Hannover, Foundation, Hannover, Germany
- Center for Systems Neuroscience, Hannover Graduate School for Neurosciences, Infection Medicine, and Veterinary Sciences (HGNI), Hannover, Germany
| | - Jeannine Biermann
- Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, Foundation, Hannover, Germany
| | - Christina Puff
- Department of Pathology, University of Veterinary Medicine Hannover, Foundation, Hannover, Germany
| | - Thomas Gerlach
- Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, Foundation, Hannover, Germany
| | - Alina Tscherne
- Division of Virology, Institute for Infectious Diseases and Zoonoses, Ludwig Maximilian University Munich, Munich, Germany
- German Center for Infection Research (DZIF), partner site Munich, Munich, Germany
| | - Wolfgang Baumgärtner
- Department of Pathology, University of Veterinary Medicine Hannover, Foundation, Hannover, Germany
- Center for Systems Neuroscience, Hannover Graduate School for Neurosciences, Infection Medicine, and Veterinary Sciences (HGNI), Hannover, Germany
| | - Albert D. M. E. Osterhaus
- Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, Foundation, Hannover, Germany
| | - Gerd Sutter
- Division of Virology, Institute for Infectious Diseases and Zoonoses, Ludwig Maximilian University Munich, Munich, Germany
- German Center for Infection Research (DZIF), partner site Munich, Munich, Germany
| | - Chittappen Kandiyil Prajeeth
- Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, Foundation, Hannover, Germany
| | - Guus F. Rimmelzwaan
- Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, Foundation, Hannover, Germany
- *Correspondence: Guus F. Rimmelzwaan,
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16
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Spread of West Nile Virus and Usutu Virus in the German Bird Population, 2019–2020. Microorganisms 2022; 10:microorganisms10040807. [PMID: 35456857 PMCID: PMC9030481 DOI: 10.3390/microorganisms10040807] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 04/04/2022] [Accepted: 04/09/2022] [Indexed: 12/21/2022] Open
Abstract
West Nile virus (WNV) and Usutu virus (USUV) are important flaviviruses circulating in Germany. While USUV was first reported more than 10 years ago, WNV has only reached the country in 2018. Wild birds are important amplifying hosts for both viruses. Therefore, we have been monitoring the bird population in different regions of Germany by a previously established network for many years. This report summarizes the results of molecular and/or serological methods of 2345 blood samples from birds of 22 different orders and over 2900 bird carcasses from 2019 and 2020. USUV RNA circulation was found in different regions of Germany, with emphasis on USUV lineages Europe 3 and Africa 3. Increased evidence of USUV lineage Europe 2 was detected in eastern Germany. WNV RNA was found only in birds from the eastern part of the country. The seroprevalence for USUV was between 3.11% and 7.20% in all three regions investigated, whereas the WNV seroprevalence spanned from 14.77% to 16.15% in eastern Germany, with a noticeable tendency for a westward and southward expansion in both years. Thus, wild bird monitoring for WNV and USUV can serve as an early warning system for a human exposure risk.
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17
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Romer Y, Adcock K, Wei Z, Mead DG, Kirstein O, Bellman S, Piantadosi A, Kitron U, Vazquez-Prokopec GM. Isolation of Heartland Virus from Lone Star Ticks, Georgia, USA, 2019. Emerg Infect Dis 2022; 28:786-792. [PMID: 35318917 PMCID: PMC8962890 DOI: 10.3201/eid2804.211540] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
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18
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Schneider WM, Hoffmann HH. Flavivirus-host interactions: an expanding network of proviral and antiviral factors. Curr Opin Virol 2022; 52:71-77. [PMID: 34896863 PMCID: PMC8655497 DOI: 10.1016/j.coviro.2021.11.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Accepted: 11/15/2021] [Indexed: 02/07/2023]
Abstract
Flaviviruses are zoonotic pathogens transmitted by the bite of infected mosquitos and ticks and represent a constant burden to human health. Here we review recent literature aimed at uncovering how flaviviruses interact with the cells that they infect. A better understanding of these interactions may ultimately lead to novel therapeutic targets. We highlight several studies that employed low-biased methods to discover new protein-protein, protein-RNA, and genetic interactions, and spotlight recent work characterizing the host protein, TMEM41B, which has been shown to be critical for infection by diverse flaviviruses and coronaviruses.
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Affiliation(s)
- William M Schneider
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA.
| | - Hans-Heinrich Hoffmann
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA.
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19
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Seroepidemiological Survey of West Nile Virus Infections in Horses from Berlin/Brandenburg and North Rhine-Westphalia, Germany. Viruses 2022; 14:v14020243. [PMID: 35215837 PMCID: PMC8877243 DOI: 10.3390/v14020243] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 01/14/2022] [Accepted: 01/21/2022] [Indexed: 02/01/2023] Open
Abstract
Following the introduction of the West Nile virus (WNV) into eastern Germany in 2018, increasing infections have been diagnosed in birds, equines, and humans over time, while the spread of WNV into western Germany remained unclear. We screened 437 equine sera from 2018 to 2020, excluding vaccinated horses, collected from convenience sampled patients in the eastern and western parts of Germany, for WNV-specific antibodies (ELISAs followed by virus/specific neutralization tests) and genomes (RT-qPCRs). Clinical presentations, final diagnoses, and demographic data were also recorded. In the eastern part, a total of eight horses were found WNV seropositive in 2019 (seroprevalence of 8.16%) and 27 in 2020 (13.77%). There were also two clinically unsuspected horses with WNV-specific antibodies in the western part from 2020 (2.63%), albeit travel history-related infections could not be excluded. None of the horse sera contained WNV-specific genomes. Eight horses in eastern Germany carried WNV-IgM antibodies, but only four of these showed typical clinical signs. These results underline the difficulty of detecting a WNV infection in a horse solely based on clinical signs. Thus, WNV circulation is established in the horse population in eastern Germany, but not yet in the western part.
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20
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Yang X, Gao GF, Liu WJ. Powassan virus: A tick borne flavivirus infecting humans. BIOSAFETY AND HEALTH 2022. [DOI: 10.1016/j.bsheal.2021.12.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022] Open
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21
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Yurayart N, Ninvilai P, Chareonviriyaphap T, Kaewamatawong T, Thontiravong A, Tiawsirisup S. Pathogenesis of Thai duck Tembusu virus in BALB/c mice: Descending infection and neuroinvasive virulence. Transbound Emerg Dis 2021; 68:3529-3540. [PMID: 33326703 DOI: 10.1111/tbed.13958] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Revised: 11/22/2020] [Accepted: 12/12/2020] [Indexed: 12/15/2022]
Abstract
Duck Tembusu virus (DTMUV) is an emerging flavivirus that causes systemic disease in an avian host. The predominant cluster of DTMUV circulating in Thailand was recently classified as cluster 2.1. The pathogenesis of this virus has been extensively studied in avian hosts but not in mammalian hosts. Six-week-old BALB/c mice were intracerebrally or subcutaneously inoculated with Thai DTMUV to examine clinical signs, pathological changes, viral load and virus distribution. Results demonstrated that the virus caused disease in BALB/c mice by the intracerebral inoculation route. Infected mice demonstrated both systemic and neurological symptoms. Pathological changes and virus distribution were observed in all tested organs. Viral load in the brain was significantly higher than in other organs (p < .05), and the virus caused acute death in BALB/c mice. The virus was disseminated in all parts of the body, but no virus shedding was recorded in saliva and faeces. Findings highlighted the potential of Thai DTMUV to transmit disease in mammalian hosts.
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Affiliation(s)
- Nichapat Yurayart
- Animal Vector-Borne Disease Research Unit, Veterinary Parasitology Unit, Department of Veterinary Pathology, Faculty of Veterinary Science, Chulalongkorn University, Bangkok, Thailand
| | - Patchareeporn Ninvilai
- Department of Veterinary Microbiology, Faculty of Veterinary Science, Chulalongkorn University, Bangkok, Thailand
| | | | - Theerayuth Kaewamatawong
- Veterinary Pathology Unit, Department of Veterinary Pathology, Faculty of Veterinary Science, Chulalongkorn University, Bangkok, Thailand
| | - Aunyaratana Thontiravong
- Animal Vector-Borne Disease Research Unit, Veterinary Parasitology Unit, Department of Veterinary Pathology, Faculty of Veterinary Science, Chulalongkorn University, Bangkok, Thailand
- Department of Veterinary Microbiology, Faculty of Veterinary Science, Chulalongkorn University, Bangkok, Thailand
| | - Sonthaya Tiawsirisup
- Animal Vector-Borne Disease Research Unit, Veterinary Parasitology Unit, Department of Veterinary Pathology, Faculty of Veterinary Science, Chulalongkorn University, Bangkok, Thailand
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22
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Eberle RJ, Olivier DS, Amaral MS, Willbold D, Arni RK, Coronado MA. Promising Natural Compounds against Flavivirus Proteases: Citrus Flavonoids Hesperetin and Hesperidin. PLANTS (BASEL, SWITZERLAND) 2021; 10:plants10102183. [PMID: 34685992 PMCID: PMC8539695 DOI: 10.3390/plants10102183] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 10/11/2021] [Accepted: 10/13/2021] [Indexed: 05/04/2023]
Abstract
Ubiquitous in citrus plants, Hesperidin and Hesperetin flavanones possess several biological functions, including antiviral activity. Arbovirus infections pose an ever-increasing threat to global healthcare systems. Among the severe arboviral infections currently known are those caused by members of the Flavivirus genus, for example, Dengue Virus-DENV, Yellow Fever Virus-YFV, and West Nile Virus-WNV. In this study, we characterize the inhibitory effect of Hesperidin and Hesperetin against DENV2, YFV, and WNV NS2B/NS3 proteases. We report the noncompetitive inhibition of the NS2B/NS3pro by the two bioflavonoids with half maximal inhibitory concentration (IC50) values <5 µM for HST and <70 µM for HSD. The determined dissociation constants (KD) of both flavonoids is significantly below the threshold value of 30 µM. Our findings demonstrate that a new generation of anti-flavivirus drugs could be developed based on selective optimization of both molecules.
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Affiliation(s)
- Raphael J. Eberle
- Institute of Biological Information Processing (IBI-7: Structural Biochemistry), Forschungszentrum Jülich, 52428 Jülich, Germany;
- Institut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf, Universitätsstraße, 40225 Düsseldorf, Germany
- Correspondence: (R.J.E.); (M.A.C.)
| | - Danilo S. Olivier
- Integrated Sciences Center, Federal University of Tocantins, Araguaína 77824-838, Brazil;
| | - Marcos S. Amaral
- Institute of Physics, Federal University of Mato Grosso do Sul, Campo Grande 79070-900, Brazil;
| | - Dieter Willbold
- Institute of Biological Information Processing (IBI-7: Structural Biochemistry), Forschungszentrum Jülich, 52428 Jülich, Germany;
- Institut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf, Universitätsstraße, 40225 Düsseldorf, Germany
- JuStruct: Jülich Centre for Structural Biology, Forchungszentrum Jülich, 52428 Jülich, Germany
| | - Raghuvir K. Arni
- Multiuser Center for Biomolecular Innovation, Departament of Physics, Universidade Estadual Paulista (UNESP), São Jose do Rio Preto 15054-000, Brazil;
| | - Monika A. Coronado
- Institute of Biological Information Processing (IBI-7: Structural Biochemistry), Forschungszentrum Jülich, 52428 Jülich, Germany;
- Correspondence: (R.J.E.); (M.A.C.)
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23
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Gudowska-Sawczuk M, Mroczko B. Selected Biomarkers of Tick-Borne Encephalitis: A Review. Int J Mol Sci 2021; 22:10615. [PMID: 34638953 PMCID: PMC8509006 DOI: 10.3390/ijms221910615] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Revised: 09/13/2021] [Accepted: 09/27/2021] [Indexed: 12/30/2022] Open
Abstract
Tick-borne encephalitis (TBE) is an acute disease caused by the tick-borne encephalitis virus. Due to the viral nature of the condition, there is no effective causal treatment for full-blown disease. Current and nonspecific TBE treatments only relieve symptoms. Unfortunately, the first phase of TBE is characterized by flu-like symptoms, making diagnosis difficult during this period. The second phase is referred to as the neurological phase as it involves structures in the central nervous system-most commonly the meninges and, in more severe cases, the brain and the spinal cord. Therefore, it is important that early markers of TBE that will guide clinical decision-making and the choice of treatment are established. In this review, we performed an extensive search of literature reports relevant to biomarkers associated with TBE using the MEDLINE/PubMed database. We observed that apart from routinely determined specific immunoglobulins, free light chains may also be useful in the evaluation of intrathecal synthesis in the central nervous system (CNS) during TBEV infection. Moreover, selected metalloproteinases, chemokines, or cytokines appear to play an important role in the pathogenesis of TBE as a consequence of inflammatory reactions and recruitment of white blood cells into the CNS. Furthermore, we reported promising findings on tau protein or Toll-like receptors. It was also observed that some people may be predisposed to TBE. Therefore, to understand the role of selected tick-borne encephalitis biomarkers, we categorized these factors and discussed their potential application in the diagnosis, prognosis, monitoring, or management of TBE.
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Affiliation(s)
- Monika Gudowska-Sawczuk
- Department of Biochemical Diagnostics, Medical University of Bialystok, ul. Waszyngtona 15A, 15-269 Bialystok, Poland;
| | - Barbara Mroczko
- Department of Biochemical Diagnostics, Medical University of Bialystok, ul. Waszyngtona 15A, 15-269 Bialystok, Poland;
- Department of Neurodegeneration Diagnostics, Medical University of Bialystok, ul. Waszyngtona 15A, 15-269 Bialystok, Poland
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24
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Glud HA, George S, Skovgaard K, Larsen LE. Zoonotic and reverse zoonotic transmission of viruses between humans and pigs. APMIS 2021; 129:675-693. [PMID: 34586648 PMCID: PMC9297979 DOI: 10.1111/apm.13178] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Accepted: 08/28/2021] [Indexed: 12/30/2022]
Abstract
Humans and pigs share a close contact relationship, similar biological traits, and one of the highest estimated number of viruses compared to other mammalian species. The contribution and directionality of viral exchange between humans and pigs remain unclear for some of these viruses, but their transmission routes are important to characterize in order to prevent outbreaks of disease in both host species. This review collects and assesses the evidence to determine the likely transmission route of 27 viruses between humans and pigs.
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Affiliation(s)
- Helena Aagaard Glud
- Department of Biotechnology and Biomedicine, Technical University of Denmark, Kongens Lyngby, Denmark
| | - Sophie George
- Department of Veterinary and Animal Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Kerstin Skovgaard
- Department of Biotechnology and Biomedicine, Technical University of Denmark, Kongens Lyngby, Denmark
| | - Lars Erik Larsen
- Department of Veterinary and Animal Sciences, University of Copenhagen, Copenhagen, Denmark
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25
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Development and Characterization of SYBR Green I Based RT-PCR Assay for Detection of Omsk Hemorrhagic Fever Virus. Virol Sin 2021; 36:1644-1647. [PMID: 34076867 DOI: 10.1007/s12250-021-00389-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Accepted: 03/17/2021] [Indexed: 10/21/2022] Open
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26
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Chitimia-Dobler L, Lindau A, Oehme R, Bestehorn-Willmann M, Antwerpen M, Drehmann M, Hierl T, Mackenstedt U, Dobler G. Tick-Borne Encephalitis Vaccination Protects from Alimentary TBE Infection: Results from an Alimentary Outbreak. Microorganisms 2021; 9:microorganisms9050889. [PMID: 33919318 PMCID: PMC8143337 DOI: 10.3390/microorganisms9050889] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 04/14/2021] [Accepted: 04/18/2021] [Indexed: 12/22/2022] Open
Abstract
In May 2017, a hospitalized index case of tick-borne encephalitis (TBE) was confirmed by Serology. The case was linked to alimentary infection by raw milk from a goat farm in the region of Tübingen, Baden-Württemberg, Germany, where no previous TBE cases in the area had been reported before. The TBE focus was confirmed by isolation of the TBE virus from ticks and Serological confirmation of past infection in one of the five flock goats. Additional investigations by the local public health office identified 27 consumers of goat milk at the putative period of exposure. For 20/27 exposed persons, anamnestic information was gained by the local public health office. Twelve/fourteen exposed and non-vaccinated people developed clinical illness and were confirmed as TBE cases by Serology. Five/six vaccinated and exposed people did not develop the disease. The one exposed and vaccinated person had their last TBE vaccination booster more than 15 years ago, and therefore a booster was more than 10 years overdue. None of the regularly vaccinated and exposed persons developed clinical overt TBE infection. We report the first known TBE outbreak, during which, protection by TBE vaccination against alimentary TBE infection was demonstrated.
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Affiliation(s)
- Lidia Chitimia-Dobler
- Bundeswehr Institute of Microbiology, 80937 Munich, Germany; (L.C.-D.); (M.A.)
- Department of Parasitology, University of Hohenheim, 70599 Stuttgart, Germany; (A.L.); (M.B.-W.); (M.D.); (U.M.)
| | - Alexander Lindau
- Department of Parasitology, University of Hohenheim, 70599 Stuttgart, Germany; (A.L.); (M.B.-W.); (M.D.); (U.M.)
| | - Rainer Oehme
- State Health Office Baden-Württemberg, 70191 Stuttgart, Germany;
| | - Malena Bestehorn-Willmann
- Department of Parasitology, University of Hohenheim, 70599 Stuttgart, Germany; (A.L.); (M.B.-W.); (M.D.); (U.M.)
| | - Markus Antwerpen
- Bundeswehr Institute of Microbiology, 80937 Munich, Germany; (L.C.-D.); (M.A.)
| | - Marco Drehmann
- Department of Parasitology, University of Hohenheim, 70599 Stuttgart, Germany; (A.L.); (M.B.-W.); (M.D.); (U.M.)
| | - Thomas Hierl
- District Health Office Zollernalbkreis, 72379 Hechingen, Germany;
| | - Ute Mackenstedt
- Department of Parasitology, University of Hohenheim, 70599 Stuttgart, Germany; (A.L.); (M.B.-W.); (M.D.); (U.M.)
| | - Gerhard Dobler
- Bundeswehr Institute of Microbiology, 80937 Munich, Germany; (L.C.-D.); (M.A.)
- Department of Parasitology, University of Hohenheim, 70599 Stuttgart, Germany; (A.L.); (M.B.-W.); (M.D.); (U.M.)
- Correspondence: ; Tel.: +49-899926923974
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27
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Blasdell KR, Wynne JW, Perera D, Firth C. First detection of a novel 'unknown host' flavivirus in a Malaysian rodent. Access Microbiol 2021; 3:000223. [PMID: 34151174 PMCID: PMC8208762 DOI: 10.1099/acmi.0.000223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Accepted: 03/22/2021] [Indexed: 11/18/2022] Open
Abstract
Current phylogenetic analysis of the flavivirus genus has identified a group of mosquito-borne viruses for which the vertebrate hosts are currently unknown. Here we report the identification of a novel member of this group from a peridomestic rodent species (Sundamys muelleri) collected in Sarawak, Malaysia in 2016. We propose to name this novel flavivirus Batu Kawa virus after the location in which it was identified, with the abbreviation BKWV. Characterization of the BKWV genome allowed identification of putative mature peptides, potential enzyme motifs and conserved structural elements. Phylogenetic analysis found BKWV to be most closely related to Nhumirim virus (from Brazil) and Barkedji virus (from Senegal and Israel). Both of these viruses have been identified in Culex mosquitoes and belong to a group of viruses with unknown vertebrate hosts. This is the first known report of a member of this group of viruses from a potential mammalian host.
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Affiliation(s)
- Kim R Blasdell
- Health and Biosecurity Business Unit, Commonwealth Scientific and Industrial Research Organisation, Geelong, Victoria, Australia
| | - James W Wynne
- Agriculture and Food Business Unit, Commonwealth Scientific and Industrial Research Organisation, Hobart, Tasmania, Australia
| | - David Perera
- The Institute of Health and Community Medicine, Universiti Malaysia Sarawak, Kota Samarahan, Sarawak, Malaysia
| | - Cadhla Firth
- Health and Biosecurity Business Unit, Commonwealth Scientific and Industrial Research Organisation, Geelong, Victoria, Australia.,Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Australia
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28
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Negi T, Kandari LS, Arunachalam K. Update on prevalence and distribution pattern of tick-borne diseases among humans in India: a review. Parasitol Res 2021; 120:1523-1539. [PMID: 33797610 DOI: 10.1007/s00436-021-07114-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Accepted: 03/03/2021] [Indexed: 11/26/2022]
Abstract
In the present scenario, tick-borne diseases (TBDs) are well known for their negative impacts on humans as well as animal health in India. The reason lies in their increased incidences due to global warming, environmental and ecological changes, and availability of suitable habitats. On a global basis, they are now considered a serious threat to human as well as livestock health. The major tick-borne diseases in India include Kyasanur forest disease (KFD), Crimean-congo hemorrhagic fever (CCHF), Lyme disease (LD), Q fever (also known as coxiellosis), and Rickettsial infections. In recent years, other tick-borne diseases such as Babesiosis, Ganjam virus (GANV), and Bhanja virus (BHAV) infections have also been reported in India. The purpose of this paper is to review the history and the current state of knowledge of tick-borne diseases in the country. The conclusion of this review is extending the requirement of greater efforts in research and government management for the diagnosis and treatment and as well as prevention of these diseases so that tick-borne disease burden should be minimizing in India.
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Affiliation(s)
- Tripti Negi
- School of Environment and Natural Resources, Doon University, Dehradun, Uttarakhand, 248 012, India.
| | - Laxman Singh Kandari
- Department of Forestry and Natural Resources, School of Agriculture and Allied Science, HNB Garhwal University, Srinagar, Uttarakhand, 246 174, India
| | - Kusum Arunachalam
- School of Environment and Natural Resources, Doon University, Dehradun, Uttarakhand, 248 012, India
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29
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Phylogenetic analysis of tick-borne encephalitis virus strains found in an engorged tick and traveler returning from Russia. Ticks Tick Borne Dis 2021; 12:101670. [PMID: 33571754 DOI: 10.1016/j.ttbdis.2021.101670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 01/11/2021] [Accepted: 01/12/2021] [Indexed: 11/22/2022]
Abstract
Although travel-related tick-borne encephalitis (TBE) cases have been increasingly registered worldwide, very few published case studies are available to date. The present report describes a travel-related TBE case and provides genotypic characterization of two viral isolates. Laboratory diagnostics were based on complement fixation test and virus isolation. This report is unique because the TBE case was first confirmed by virus isolation from the engorged tick and only later from the patient's blood. Moreover, this case demonstrated a successful prophylaxis performed on day 8 post tick exposure although it is generally recommended that anti-TBEV immunoglobulins should be administered not later than on day 4 after tick bite. Sequences of E protein gene fragments were used to phylogenetically characterize the two isolates. The results demonstrated that both viral isolates belonged to clusteron 3A (Zausaev group) of the Asian lineage of the TBEV Siberian subtype. The synonymous nucleotide substitution, C351 T, was identified in E protein gene fragments of TBEV 88 and TBEV 89, which could have been induced by virus transmission. A few important take-home messages can be gleaned from the reported case. First, travelers should be aware of TBE endemic areas that they plan to visit and be proactive when exposed to Ixodes ticks. Second, medical practitioners should always consider travel history and potential tick exposure of patients. Lastly, engorged Ixodes spp. ticks removed from the patients, who have arrived from endemic areas, should be tested for TBEV even in the absence of TBE clinical signs.
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Hoffmann HH, Schneider WM, Rozen-Gagnon K, Miles LA, Schuster F, Razooky B, Jacobson E, Wu X, Yi S, Rudin CM, MacDonald MR, McMullan LK, Poirier JT, Rice CM. TMEM41B Is a Pan-flavivirus Host Factor. Cell 2021; 184:133-148.e20. [PMID: 33338421 PMCID: PMC7954666 DOI: 10.1016/j.cell.2020.12.005] [Citation(s) in RCA: 135] [Impact Index Per Article: 33.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 11/13/2020] [Accepted: 12/02/2020] [Indexed: 12/12/2022]
Abstract
Flaviviruses pose a constant threat to human health. These RNA viruses are transmitted by the bite of infected mosquitoes and ticks and regularly cause outbreaks. To identify host factors required for flavivirus infection, we performed full-genome loss of function CRISPR-Cas9 screens. Based on these results, we focused our efforts on characterizing the roles that TMEM41B and VMP1 play in the virus replication cycle. Our mechanistic studies on TMEM41B revealed that all members of the Flaviviridae family that we tested require TMEM41B. We tested 12 additional virus families and found that SARS-CoV-2 of the Coronaviridae also required TMEM41B for infection. Remarkably, single nucleotide polymorphisms present at nearly 20% in East Asian populations reduce flavivirus infection. Based on our mechanistic studies, we propose that TMEM41B is recruited to flavivirus RNA replication complexes to facilitate membrane curvature, which creates a protected environment for viral genome replication.
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Affiliation(s)
- H-Heinrich Hoffmann
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA
| | - William M Schneider
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA
| | - Kathryn Rozen-Gagnon
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA
| | - Linde A Miles
- Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Felix Schuster
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA; Institute of Virology, Medical Faculty "Carl Gustav Carus", Technische Universität Dresden, Dresden, Germany
| | - Brandon Razooky
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA
| | - Eliana Jacobson
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA
| | - Xianfang Wu
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA
| | - Soon Yi
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA
| | - Charles M Rudin
- Druckenmiller Center for Lung Cancer Research and Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Margaret R MacDonald
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA
| | - Laura K McMullan
- Virus Special Pathogens Branch, Division of High Consequence Pathogens and Pathology, Centers of Disease Control and Prevention, Atlanta, GA, USA
| | - John T Poirier
- Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY, USA.
| | - Charles M Rice
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA.
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Radzišauskienė D, Urbonienė J, Kaubrys G, Andruškevičius S, Jatužis D, Matulytė E, Žvirblytė-Skrebutienė K. The epidemiology, clinical presentation, and predictors of severe Tick-borne encephalitis in Lithuania, a highly endemic country: A retrospective study of 1040 patients. PLoS One 2020; 15:e0241587. [PMID: 33211708 PMCID: PMC7676731 DOI: 10.1371/journal.pone.0241587] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Accepted: 10/17/2020] [Indexed: 12/11/2022] Open
Abstract
Introduction In recent decades, the incidence of Tick-borne encephalitis (TBE) has been increasing and posing a growing health problem because of the high costs to the healthcare system and society. The clinical manifestations are well studied but there is a lack of research analyzing the severity of the disease. Objective The aim of this study was to analyze the epidemiology and clinical presentation of severe TBE, to identify the predictors for a severe disease course, and also predictors for meningoencephalomyelitic and severe meningoencephalitic/encephalitic forms. Methods A retrospective study was conducted in the Center of Infectious Diseases and the Center of Neurology at Vilnius University Hospital Santaros Klinikos in the years 2005–2017 to describe the clinical and epidemiological features of TBE in adults. Results 1040 patients were included in the study. A total of 152/1040 (14.6%) patients had a severe course. The highest proportion of severe cases, reaching 41.2%, was reported in the 70–79 year-old age group. A total of 36/152 (23.7%) severe patients presented meningoencephalomyelitis. Myelitic patients were older, were frequently infected in their living areas, and usually reported a monophasic disease course compared with severe meningoencephalitic/encephalitic patients. Severe meningoencephalitic/encephalitic patients, compared with non-severe meningoencephalitic/encephalitic, were older, less often noticed the tick bite, and often had a monophasic course. The sequelae on discharge were observed in 810/1000 (81%) of patients. Conclusions The prognostic factors associated with a severe disease course and severe meningoencephalitic form are: older age, comorbidities, a monophasic course, a fever of 40˚C and above, CRP more than 30 mg/l, CSF protein more than 1 g/l, delayed immune response of TBEV IgG, pathological findings in CT. Age above 60 years, presence of CNS disease, bulbar syndrome, pleocytosis 500x106/l and above, and delayed immune response of TBEV IgG are predictors of the most severe myelitic form.
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Affiliation(s)
- Daiva Radzišauskienė
- Clinic of Infectious Diseases and Dermatovenerology, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
- * E-mail:
| | - Jurgita Urbonienė
- Center of Infectious Diseases, Vilnius University, Vilnius, Lithuania
| | - Gintaras Kaubrys
- Clinic of Neurology and Neurosurgery, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| | - Saulius Andruškevičius
- Clinic of Neurology and Neurosurgery, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| | - Dalius Jatužis
- Clinic of Neurology and Neurosurgery, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| | - Elžbieta Matulytė
- Clinic of Infectious Diseases and Dermatovenerology, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| | - Karolina Žvirblytė-Skrebutienė
- Clinic of Infectious Diseases and Dermatovenerology, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
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Hoffmann HH, Schneider WM, Rozen-Gagnon K, Miles LA, Schuster F, Razooky B, Jacobson E, Wu X, Yi S, Rudin CM, MacDonald MR, McMullan LK, Poirier JT, Rice CM. TMEM41B is a pan-flavivirus host factor. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2020:2020.10.09.334128. [PMID: 33052348 PMCID: PMC7553181 DOI: 10.1101/2020.10.09.334128] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Flaviviruses pose a constant threat to human health. These RNA viruses are transmitted by the bite of infected mosquitoes and ticks and regularly cause outbreaks. To identify host factors required for flavivirus infection we performed full-genome loss of function CRISPR-Cas9 screens. Based on these results we focused our efforts on characterizing the roles that TMEM41B and VMP1 play in the virus replication cycle. Our mechanistic studies on TMEM41B revealed that all members of the Flaviviridae family that we tested require TMEM41B. We tested 12 additional virus families and found that SARS-CoV-2 of the Coronaviridae also required TMEM41B for infection. Remarkably, single nucleotide polymorphisms (SNPs) present at nearly twenty percent in East Asian populations reduce flavivirus infection. Based on our mechanistic studies we hypothesize that TMEM41B is recruited to flavivirus RNA replication complexes to facilitate membrane curvature, which creates a protected environment for viral genome replication. HIGHLIGHTS TMEM41B and VMP1 are required for both autophagy and flavivirus infection, however, autophagy is not required for flavivirus infection.TMEM41B associates with viral proteins and likely facilitates membrane remodeling to establish viral RNA replication complexes.TMEM41B single nucleotide polymorphisms (SNPs) present at nearly twenty percent in East Asian populations reduce flavivirus infection.TMEM41B-deficient cells display an exaggerated innate immune response upon high multiplicity flavivirus infection.
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Affiliation(s)
- H-Heinrich Hoffmann
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA
| | - William M Schneider
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA
| | - Kathryn Rozen-Gagnon
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA
| | - Linde A Miles
- Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Felix Schuster
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA
- Institute of Virology, Medical Faculty "Carl Gustav Carus", Technische Universität Dresden, Dresden, Germany
| | - Brandon Razooky
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA
| | - Eliana Jacobson
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA
| | - Xianfang Wu
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA
| | - Soon Yi
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA
| | - Charles M Rudin
- Druckenmiller Center for Lung Cancer Research and Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Margaret R MacDonald
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA
| | - Laura K McMullan
- Virus Special Pathogens Branch, Division of High Consequence Pathogens and Pathology, Centers of Disease Control and Prevention, Atlanta, GA, USA
| | - John T Poirier
- Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY, USA
| | - Charles M Rice
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA
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Abdiyeva K, Turebekov N, Yegemberdiyeva R, Dmitrovskiy A, Yeraliyeva L, Shapiyeva Z, Nurmakhanov T, Sansyzbayev Y, Froeschl G, Hoelscher M, Zinner J, Essbauer S, Frey S. Vectors, molecular epidemiology and phylogeny of TBEV in Kazakhstan and central Asia. Parasit Vectors 2020; 13:504. [PMID: 33023633 PMCID: PMC7539389 DOI: 10.1186/s13071-020-04362-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Accepted: 09/15/2020] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND In the South of Kazakhstan, Almaty Oblast' (region) is endemic for tick-borne encephalitis, with 0.16-0.32 cases/100,000 population between 2016-2018. The purpose of this study was to determine the prevalence and circulating subtypes of tick-borne encephalitis virus (TBEV) in Almaty Oblast' and Kyzylorda Oblast'. METHODS In 2015 we investigated 2341 ticks from 7 sampling sites for the presence of TBEV. Ticks were pooled in 501 pools and isolated RNA was tested for the presence of TBEV by RT-qPCR. For the positive samples, the E gene was amplified, sequenced and a phylogenetic analysis was carried out. RESULTS A total of 48 pools were TBEV-positive by the RT-qPCR. TBEV-positive ticks were only detected in three districts of Almaty Oblast' and not in Kyzylorda Oblast'. The positive TBEV pools were found within Ixodes persulcatus, Haemaphysalis punctata and Dermacentor marginatus. These tick species prevailed only in Almaty Oblast' whereas in Kyzylorda Oblast' Hyalomma asiaticum and D. marginatus are endemic. The minimum infection rates (MIR) in the sampling sites were 4.4% in Talgar, 2.8% in Tekeli and 1.1% in Yenbekshikazakh, respectively. The phylogenetic analysis of the generated sequences indicates that TBEV strains found in Almaty Oblast' clusters in the Siberian subtype within two different clades. CONCLUSIONS We provided new data about the TBEV MIR in ticks in Almaty Oblast' and showed that TBEV clusters in the Siberian Subtype in two different clusters at the nucleotide level. These results indicate that there are different influences on the circulating TBEV strains in south-eastern Kazakhstan. These influences might be caused by different routes of the virus spread in ticks which might bring different genetic TBEV lineages to Kazakhstan. The new data about the virus distribution and vectors provided here will contribute to an improvement of monitoring of tick-borne infections and timely anti-epidemic measures in Kazakhstan.
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Affiliation(s)
- Karlygash Abdiyeva
- Center for International Health, Ludwig-Maximilians-Universität, Munich, Germany
- National Scientific Center for Highly Dangerous Infections, Almaty, Kazakhstan
| | - Nurkeldi Turebekov
- Center for International Health, Ludwig-Maximilians-Universität, Munich, Germany
- National Scientific Center for Highly Dangerous Infections, Almaty, Kazakhstan
| | | | | | | | - Zhanna Shapiyeva
- Scientific Practical Center of Sanitary Epidemiological Expertise and Monitoring, Almaty, Kazakhstan
| | - Talgat Nurmakhanov
- National Scientific Center for Highly Dangerous Infections, Almaty, Kazakhstan
| | - Yerlan Sansyzbayev
- National Scientific Center for Highly Dangerous Infections, Almaty, Kazakhstan
| | - Guenter Froeschl
- Center for International Health, Ludwig-Maximilians-Universität, Munich, Germany
- Division of Infectious Diseases and Tropical Medicine, University Hospital, LMU Munich, Munich, Germany
| | - Michael Hoelscher
- Division of Infectious Diseases and Tropical Medicine, University Hospital, LMU Munich, Munich, Germany
| | | | | | - Stefan Frey
- Institute of Microbiology, Munich, Germany
- present Address: Bundeswehr Research Institute for Protective Technologies and CBRN Protection, Munster, Germany
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Clark JJ, Gilray J, Orton RJ, Baird M, Wilkie G, Filipe ADS, Johnson N, McInnes CJ, Kohl A, Biek R. Population genomics of louping ill virus provide new insights into the evolution of tick-borne flaviviruses. PLoS Negl Trop Dis 2020; 14:e0008133. [PMID: 32925939 PMCID: PMC7515184 DOI: 10.1371/journal.pntd.0008133] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 09/24/2020] [Accepted: 08/07/2020] [Indexed: 12/30/2022] Open
Abstract
The emergence and spread of tick-borne arboviruses pose an increased challenge to human and animal health. In Europe this is demonstrated by the increasingly wide distribution of tick-borne encephalitis virus (TBEV, Flavivirus, Flaviviridae), which has recently been found in the United Kingdom (UK). However, much less is known about other tick-borne flaviviruses (TBFV), such as the closely related louping ill virus (LIV), an animal pathogen which is endemic to the UK and Ireland, but which has been detected in other parts of Europe including Scandinavia and Russia. The emergence and potential spatial overlap of these viruses necessitates improved understanding of LIV genomic diversity, geographic spread and evolutionary history. We sequenced a virus archive composed of 22 LIV isolates which had been sampled throughout the UK over a period of over 80 years. Combining this dataset with published virus sequences, we detected no sign of recombination and found low diversity and limited evidence for positive selection in the LIV genome. Phylogenetic analysis provided evidence of geographic clustering as well as long-distance movement, including movement events that appear recent. However, despite genomic data and an 80-year time span, we found that the data contained insufficient temporal signal to reliably estimate a molecular clock rate for LIV. Additional analyses revealed that this also applied to TBEV, albeit to a lesser extent, pointing to a general problem with phylogenetic dating for TBFV. The 22 LIV genomes generated during this study provide a more reliable LIV phylogeny, improving our knowledge of the evolution of tick-borne flaviviruses. Our inability to estimate a molecular clock rate for both LIV and TBEV suggests that temporal calibration of tick-borne flavivirus evolution should be interpreted with caution and highlight a unique aspect of these viruses which may be explained by their reliance on tick vectors. Tick-borne pathogens represent a major emerging threat to public health and in recent years have been expanding into new areas. LIV is a neglected virus endemic to the UK and Ireland (though it has been detected in Scandinavia and Russia) which is closely related to the major human pathogen TBEV, but predominantly causes disease in sheep and grouse. The recent detection of TBEV in the UK, which has also emerged elsewhere in Europe, requires more detailed understanding of the spread and sequence diversity of LIV. This could be important for diagnosis and vaccination, but also to improve our understanding of the evolution and emergence of these tick-borne viruses. Here we describe the sequencing of 22 LIV isolates which have been sampled from several host species across the past century. We have utilised this dataset to investigate the evolutionary pressures that LIV is subjected to and have explored the evolution of LIV using phylogenetic analysis. Crucially we were unable to estimate a reliable molecular clock rate for LIV and found that this problem also extends to a larger phylogeny of TBEV sequences. This work highlights a previously unknown caveat of tick-borne flavivirus evolutionary analysis which may be important for understanding the evolution of these important pathogens.
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Affiliation(s)
- Jordan J. Clark
- MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom
- Moredun Research Institute, Edinburgh, United Kingdom
- * E-mail: (JC); (RB)
| | - Janice Gilray
- Moredun Research Institute, Edinburgh, United Kingdom
| | - Richard J. Orton
- MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom
| | - Margaret Baird
- MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom
| | - Gavin Wilkie
- MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom
| | - Ana da Silva Filipe
- MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom
| | - Nicholas Johnson
- Animal and Plant Health Agency, Addlestone, Surrey, United Kingdom
- Faculty of Health and Medical Science, University of Surrey, Guildford, Surrey, United Kingdom
| | | | - Alain Kohl
- MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom
| | - Roman Biek
- Institute of Biodiversity, Animal Health and Comparative Medicine - University of Glasgow, Glasgow, United Kingdom
- * E-mail: (JC); (RB)
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Kubinski M, Beicht J, Gerlach T, Volz A, Sutter G, Rimmelzwaan GF. Tick-Borne Encephalitis Virus: A Quest for Better Vaccines against a Virus on the Rise. Vaccines (Basel) 2020; 8:E451. [PMID: 32806696 PMCID: PMC7564546 DOI: 10.3390/vaccines8030451] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 08/06/2020] [Accepted: 08/10/2020] [Indexed: 12/15/2022] Open
Abstract
Tick-borne encephalitis virus (TBEV), a member of the family Flaviviridae, is one of the most important tick-transmitted viruses in Europe and Asia. Being a neurotropic virus, TBEV causes infection of the central nervous system, leading to various (permanent) neurological disorders summarized as tick-borne encephalitis (TBE). The incidence of TBE cases has increased due to the expansion of TBEV and its vectors. Since antiviral treatment is lacking, vaccination against TBEV is the most important protective measure. However, vaccination coverage is relatively low and immunogenicity of the currently available vaccines is limited, which may account for the vaccine failures that are observed. Understanding the TBEV-specific correlates of protection is of pivotal importance for developing novel and improved TBEV vaccines. For affording robust protection against infection and development of TBE, vaccines should induce both humoral and cellular immunity. In this review, the adaptive immunity induced upon TBEV infection and vaccination as well as novel approaches to produce improved TBEV vaccines are discussed.
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Affiliation(s)
- Mareike Kubinski
- Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Foundation (TiHo), Buenteweg 17, 30559 Hannover, Germany; (M.K.); (J.B.); (T.G.)
| | - Jana Beicht
- Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Foundation (TiHo), Buenteweg 17, 30559 Hannover, Germany; (M.K.); (J.B.); (T.G.)
| | - Thomas Gerlach
- Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Foundation (TiHo), Buenteweg 17, 30559 Hannover, Germany; (M.K.); (J.B.); (T.G.)
| | - Asisa Volz
- Institute of Virology, University of Veterinary Medicine Hannover, Foundation (TiHo), Buenteweg 17, 30559 Hannover, Germany;
| | - Gerd Sutter
- Institute for Infectious Diseases and Zoonoses, Ludwig-Maximilians-University (LMU) Munich, Veterinaerstr. 13, 80539 Munich, Germany;
| | - Guus F. Rimmelzwaan
- Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Foundation (TiHo), Buenteweg 17, 30559 Hannover, Germany; (M.K.); (J.B.); (T.G.)
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Iannetta M, Di Caro A, Nicastri E, Vairo F, Masanja H, Kobinger G, Mirazimi A, Ntoumi F, Zumla A, Ippolito G. Viral Hemorrhagic Fevers Other than Ebola and Lassa. Infect Dis Clin North Am 2020; 33:977-1002. [PMID: 31668201 DOI: 10.1016/j.idc.2019.08.003] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Viral hemorrhagic fevers represent a group of diseases caused by enveloped RNA viruses. The epidemiology is broadly variable, ranging from geographically localized to more diffuse infections. Viral hemorrhagic fevers are classified as category A bioweapon agents by the Centers for Disease Control and Prevention. Viral hemorrhagic fevers are severe febrile illnesses with hemorrhagic phenomena. Laboratory diagnosis takes place in highly specialized reference laboratories. Treatment is essentially supportive. In this article, we focus the attention on yellow fever and viral hemorrhagic fevers other than Ebola and Lassa virus diseases that have been described elsewhere in this issue.
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Affiliation(s)
- Marco Iannetta
- National Institute for Infectious Diseases, Lazzaro Spallanzani, IRCCS, Via Portuense 292, Rome 00149, Italy
| | - Antonino Di Caro
- National Institute for Infectious Diseases, Lazzaro Spallanzani, IRCCS, Via Portuense 292, Rome 00149, Italy
| | - Emanuele Nicastri
- National Institute for Infectious Diseases, Lazzaro Spallanzani, IRCCS, Via Portuense 292, Rome 00149, Italy
| | - Francesco Vairo
- National Institute for Infectious Diseases, Lazzaro Spallanzani, IRCCS, Via Portuense 292, Rome 00149, Italy
| | - Honorati Masanja
- Ifakara Health Institute, Ifakara Health Research and Development Centre, Kiko Avenue, Plot N 463, Mikocheni, Dar es Salaam, Tanzania
| | - Gary Kobinger
- Centre de Recherche en Infectiologie, Centre Hospitalier Universitaire de Québec, Université Laval, 2325 Rue de l'Université, Quebec City, Quebec G1V 0A6, Canada
| | - Ali Mirazimi
- Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Alfred Nobels Alle 8 Plan 7, Stockholm 14183, Sweden
| | - Francine Ntoumi
- Université Marien NGouabi, Fondation Congolaise pour la Recherche Médicale (FCRM), Villa D6, Campus OMS//AFRO Djoué, Brazzaville, Congo; Institute for Tropical Medicine, University of Tübingen, Germany
| | - Alimuddin Zumla
- Center for Clinical Microbiology, University College London, Royal Free Campus 2nd Floor, Rowland Hill Street, London NW3 2PF, United Kingdom
| | - Giuseppe Ippolito
- National Institute for Infectious Diseases, Lazzaro Spallanzani, IRCCS, Via Portuense 292, Rome 00149, Italy.
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The Seroprevalence of Tick-Borne Encephalitis in Rural Population of Mazandaran Province, Northern Iran (2018 - 2019). ARCHIVES OF CLINICAL INFECTIOUS DISEASES 2020. [DOI: 10.5812/archcid.98867] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Aguilar-Tipacamu G, Carvajal-Gamez BI, García-Rejon J, Machain-Willians C, Mosqueda J. Immuno-molecular prospecting for vector-borne diseases in central Mexico. Transbound Emerg Dis 2020; 67 Suppl 2:185-192. [PMID: 32090486 DOI: 10.1111/tbed.13504] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Climatic changes have influenced the temporal and spatial distribution of diseases. In livestock-grazing areas, rodents are reservoirs of zoonotic pathogens; therefore, they play an important role in the transmission of diseases affecting domestic animals and humans. The objective of this study was to investigate the presence of the zoonotic agents: Anaplasma phagocytophilum, Borrelia burgdorferi, Ehrlichia canis and Rickettsia rickettsii, as well as the presence of viral RNA from the Bunyaviridae, Togaviridae and Flaviviridae families, in wild rodents from animal production units in central Mexico. The samples were obtained from wild rodents that had access and contact with animal production units. A total of 92 rodents were captured, and samples of blood, serum and organs, such as spleen, kidney, heart and liver, were obtained. The serum was used to detect antibodies against Anaplasma phagocytophilum, Borrelia burgdorferi, Ehrlichia canis and Rickettsia rickettsii by an immunofluorescence antibody test (IFAT); the blood was used for PCR analysis; and the organs were used to obtain RNA (cDNA) to perform RT-PCR. By IFAT, all samples were positive to A. phagocytophilum and E. canis, and negative to B. burgdorferi and R. rickettsii. The samples that were positive to IFAT were used to confirm the presence of pathogen by PCR analysis. The results from the PCR were as follows: 34 samples were positive to A. phagocytophilum, and 59 to E. canis. There was no amplification of genetic material from the Bunyaviridae, Flaviviridae and Togaviridae virus families from the organs that were sampled, which suggests that the samples obtained did not contain RNA specific to these families. This is the first immuno-molecular prospecting study on vector-borne diseases in central Mexico demonstrating the presence of A. phagocytophilum and E. canis in wild rodents living in cattle grazing areas.
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Affiliation(s)
- Gabriela Aguilar-Tipacamu
- C. A. Salud Animal y Microbiologia Ambiental, Facultad de Ciencias Naturales, Universidad Autonoma de Queretaro, Queretaro, Mexico
| | - Bertha I Carvajal-Gamez
- Immunology and Vaccines Laboratory, C. A. Facultad de Ciencias Naturales, Universidad Autónoma de Querétaro, Queretaro, Mexico
| | - Julian García-Rejon
- Laboratorio de Arbovirología, Centro de Investigaciones Regionales Dr. Hideyo Noguchi, Universidad Autonoma de Yucatán, Merida, Mexico
| | - Carlos Machain-Willians
- Laboratorio de Arbovirología, Centro de Investigaciones Regionales Dr. Hideyo Noguchi, Universidad Autonoma de Yucatán, Merida, Mexico
| | - Juan Mosqueda
- C. A. Salud Animal y Microbiologia Ambiental, Facultad de Ciencias Naturales, Universidad Autonoma de Queretaro, Queretaro, Mexico.,Immunology and Vaccines Laboratory, C. A. Facultad de Ciencias Naturales, Universidad Autónoma de Querétaro, Queretaro, Mexico
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Maestas LP, McGay PJ, Reeser SR. Asian Longhorned Tick (Haemaphysalis longicornis) Detected in New Castle and Kent Counties, Delaware. Northeast Nat (Steuben) 2020. [DOI: 10.1656/045.027.0106] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Affiliation(s)
- Lauren P. Maestas
- Delaware Division of Fish and Wildlife, Mosquito Control Section, 2430 Old County Road, Newark, DE 19702
| | - Patrick, J. McGay
- Delaware Division of Fish and Wildlife, Mosquito Control Section, 2430 Old County Road, Newark, DE 19702
| | - Sean R. Reeser
- Delaware Division of Fish and Wildlife, Mosquito Control Section, 2430 Old County Road, Newark, DE 19702
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40
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Martins LA, Kotál J, Bensaoud C, Chmelař J, Kotsyfakis M. Small protease inhibitors in tick saliva and salivary glands and their role in tick-host-pathogen interactions. BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS 2020; 1868:140336. [DOI: 10.1016/j.bbapap.2019.140336] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Revised: 12/04/2019] [Accepted: 12/05/2019] [Indexed: 12/22/2022]
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Bournez L, Umhang G, Faure E, Boucher JM, Boué F, Jourdain E, Sarasa M, Llorente F, Jiménez-Clavero MA, Moutailler S, Lacour SA, Lecollinet S, Beck C. Exposure of Wild Ungulates to the Usutu and Tick-Borne Encephalitis Viruses in France in 2009-2014: Evidence of Undetected Flavivirus Circulation a Decade Ago. Viruses 2019; 12:E10. [PMID: 31861683 PMCID: PMC7019733 DOI: 10.3390/v12010010] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Revised: 12/13/2019] [Accepted: 12/16/2019] [Indexed: 12/30/2022] Open
Abstract
Abstract: Flaviviruses have become increasingly important pathogens in Europe over the past few decades. A better understanding of the spatiotemporal distribution of flaviviruses in France is needed to better define risk areas and to gain knowledge of the dynamics of virus transmission cycles. Serum samples from 1014 wild boar and 758 roe deer from 16 departments (administrative units) in France collected from 2009 to 2014 were screened for flavivirus antibodies using a competitive ELISA (cELISA) technique. Serum samples found to be positive or doubtful by cELISA were then tested for antibodies directed against West Nile virus (WNV), Usutu virus (USUV), Bagaza virus (BAGV), and tick-borne encephalitis/Louping ill viruses (TBEV/LIV) by microsphere immunoassays (except BAGV) and micro-neutralization tests. USUV antibodies were detected only in southeastern and southwestern areas. TBEV/LIV antibodies were detected in serum samples from eastern, southwestern and northern departments. The results indicate continuous circulation of USUV in southern France from 2009 to 2014, which was unnoticed by the French monitoring system for bird mortality. The findings also confirm wider distribution of TBEV in the eastern part of the country than of human clinical cases. However, further studies are needed to determine the tick-borne flavivirus responsible for the seroconversion in southwestern and northern France.
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Affiliation(s)
- Laure Bournez
- Nancy Laboratory for Rabies and Wildlife, The French Agency for Food, Environmental and Occupational Health and Safety (ANSES), CS 40009 54220 Malzéville, France; (G.U.); (J.-M.B.); (F.B.)
| | - Gérald Umhang
- Nancy Laboratory for Rabies and Wildlife, The French Agency for Food, Environmental and Occupational Health and Safety (ANSES), CS 40009 54220 Malzéville, France; (G.U.); (J.-M.B.); (F.B.)
| | - Eva Faure
- National Hunters Federation, 92130 Issy-les-Moulineaux, France; (E.F.); (M.S.)
| | - Jean-Marc Boucher
- Nancy Laboratory for Rabies and Wildlife, The French Agency for Food, Environmental and Occupational Health and Safety (ANSES), CS 40009 54220 Malzéville, France; (G.U.); (J.-M.B.); (F.B.)
| | - Franck Boué
- Nancy Laboratory for Rabies and Wildlife, The French Agency for Food, Environmental and Occupational Health and Safety (ANSES), CS 40009 54220 Malzéville, France; (G.U.); (J.-M.B.); (F.B.)
| | - Elsa Jourdain
- Université Clermont Auvergne, INRAE, VetAgro Sup, Unité mixte de recherche Epidémiologie des maladies animales et zoonotiques (UMR EPIA), 63122 Saint-Genès-Champanelle, France;
| | - Mathieu Sarasa
- National Hunters Federation, 92130 Issy-les-Moulineaux, France; (E.F.); (M.S.)
- Biologie et Ecologie des Organismes et Populations Sauvages (BEOPS), 1 Esplanade Compans Caffarelli, 31000 Toulouse, France
| | - Francisco Llorente
- Centro de Investigación en Sanidad Animal, Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (INIA-CISA), 28130 Valdeolmos, Spain; (F.L.); (M.A.J.-C.)
| | - Miguel A. Jiménez-Clavero
- Centro de Investigación en Sanidad Animal, Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (INIA-CISA), 28130 Valdeolmos, Spain; (F.L.); (M.A.J.-C.)
- Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), 28029 Madrid, Spain
| | - Sara Moutailler
- Unité mixte de recherche Biologie moléculaire et Immunologie Parasitaire (UMR BIPAR), ANSES, INRAE, Ecole Nationale Vétérinaire d’Alfort, Université Paris-Est, Maisons-Alfort 94700, France;
| | - Sandrine A. Lacour
- Unité mixte de recherche (UMR) Virologie, INRAE, Ecole Nationale Vétérinaire d’Alfort, ANSES, Université Paris-Est, 94700 Maisons-Alfort, France; (S.A.L.); (S.L.); (C.B.)
| | - Sylvie Lecollinet
- Unité mixte de recherche (UMR) Virologie, INRAE, Ecole Nationale Vétérinaire d’Alfort, ANSES, Université Paris-Est, 94700 Maisons-Alfort, France; (S.A.L.); (S.L.); (C.B.)
| | - Cécile Beck
- Unité mixte de recherche (UMR) Virologie, INRAE, Ecole Nationale Vétérinaire d’Alfort, ANSES, Université Paris-Est, 94700 Maisons-Alfort, France; (S.A.L.); (S.L.); (C.B.)
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In Vivo Characterization of Tick-Borne Encephalitis Virus in Bank Voles ( Myodes glareolus). Viruses 2019; 11:v11111069. [PMID: 31731773 PMCID: PMC6893798 DOI: 10.3390/v11111069] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2019] [Revised: 11/07/2019] [Accepted: 11/13/2019] [Indexed: 12/30/2022] Open
Abstract
Tick-borne encephalitis is the most important tick-transmitted zoonotic virus infection in Eurasia, causing severe neurological symptoms in humans. The causative agent, the tick-borne encephalitis virus (TBEV), circulates between ticks and a variety of mammalian hosts. To study the interaction between TBEV and one of its suspected reservoir hosts, bank voles of the Western evolutionary lineage were inoculated subcutaneously with either one of eight TBEV strains or the related attenuated Langat virus, and were euthanized after 28 days. In addition, a subset of four strains was characterized in bank voles of the Carpathian linage. Six bank voles were inoculated per strain, and were housed together in groups of three with one uninfected in-contact animal each. Generally, most bank voles did not show any clinical signs over the course of infection. However, one infected bank vole died and three had to be euthanized prematurely, all of which had been inoculated with the identical TBEV strain (Battaune 17-H9, isolated in 2017 in Germany from a bank vole). All inoculated animals seroconverted, while none of the in-contact animals did. Viral RNA was detected via real-time RT-PCR in the whole blood samples of 31 out of 74 inoculated and surviving bank voles. The corresponding serum sample remained PCR-negative in nearly all cases (29/31). In addition, brain and/or spine samples tested positive in 11 cases, mostly correlating with a positive whole blood sample. Our findings suggest a good adaption of TBEV to bank voles, combining in most cases a low virulence phenotype with detectable virus replication and hinting at a reservoir host function of bank voles for TBEV.
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Yakass MB, Franco D, Quaye O. Suppressors of Cytokine Signaling and Protein Inhibitors of Activated Signal Transducer and Activator of Transcriptions As Therapeutic Targets in Flavivirus Infections. J Interferon Cytokine Res 2019; 40:1-18. [PMID: 31436502 DOI: 10.1089/jir.2019.0097] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Flaviviruses cause significant human diseases putting more than 400 million people at risk annually worldwide. Because of migration and improved transportation, these viruses can be found on all continents (except Antarctica). Although a majority of the viruses are endemic in the tropics, a few [West Nile virus (WNV) and tick-borne encephalitis virus (TBEV)] have shown endemicity in Europe and North America. Currently, there are vaccines for the Yellow fever virus, Japanese encephalitis virus, and TBEV, but there is no effective vaccine and/or therapy against all other flaviviruses. Although there are intensive efforts to develop vaccines for Zika viruses, dengue viruses, and WNVs, there is the need for alternative or parallel antiviral therapeutic approaches. Suppressors of cytokine signaling (SOCS) and protein inhibitors of activated signal transducer and activator of transcription (STATs; PIAS), both regulatory proteins of the Janus kinase/STAT signaling pathway, have been explored as therapeutic targets in herpes simplex and vaccinia viruses, as well as in cancer therapy. In this review, we briefly describe the function of SOCS and PIAS and their therapeutic potential in flaviviral infections. [Figure: see text].
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Affiliation(s)
- Michael Bright Yakass
- West African Centre for Cell Biology of Infectious Pathogens (WACCBIP), University of Ghana, Accra, Ghana.,Department of Biochemistry, Cell and Molecular Biology, University of Ghana, Accra, Ghana
| | | | - Osbourne Quaye
- West African Centre for Cell Biology of Infectious Pathogens (WACCBIP), University of Ghana, Accra, Ghana.,Department of Biochemistry, Cell and Molecular Biology, University of Ghana, Accra, Ghana
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44
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Michelitsch A, Wernike K, Klaus C, Dobler G, Beer M. Exploring the Reservoir Hosts of Tick-Borne Encephalitis Virus. Viruses 2019; 11:E669. [PMID: 31336624 PMCID: PMC6669706 DOI: 10.3390/v11070669] [Citation(s) in RCA: 79] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2019] [Revised: 07/17/2019] [Accepted: 07/19/2019] [Indexed: 12/20/2022] Open
Abstract
Tick-borne encephalitis virus (TBEV) is an important arbovirus, which is found across large parts of Eurasia and is considered to be a major health risk for humans. Like any other arbovirus, TBEV relies on complex interactions between vectors, reservoir hosts, and the environment for successful virus circulation. Hard ticks are the vectors for TBEV, transmitting the virus to a variety of animals. The importance of these animals in the lifecycle of TBEV is still up for debate. Large woodland animals seem to have a positive influence on virus circulation by providing a food source for adult ticks; birds are suspected to play a role in virus distribution. Bank voles and yellow-necked mice are often referred to as classical virus reservoirs, but this statement lacks strong evidence supporting their highlighted role. Other small mammals (e.g., insectivores) may also play a crucial role in virus transmission, not to mention the absence of any suspected reservoir host for non-European endemic regions. Theories highlighting the importance of the co-feeding transmission route go as far as naming ticks themselves as the true reservoir for TBEV, and mammalian hosts as a mere bridge for transmission. A deeper insight into the virus reservoir could lead to a better understanding of the development of endemic regions. The spatial distribution of TBEV is constricted to certain areas, forming natural foci that can be restricted to sizes of merely 500 square meters. The limiting factors for their occurrence are largely unknown, but a possible influence of reservoir hosts on the distribution pattern of TBE is discussed. This review aims to give an overview of the multiple factors influencing the TBEV transmission cycle, focusing on the role of virus reservoirs, and highlights the questions that are waiting to be further explored.
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Affiliation(s)
- Anna Michelitsch
- Institute of Diagnostic Virology, Friedrich-Loeffler-Institut, Südufer 10, 17493 Greifswald-Insel Riems, Germany
| | - Kerstin Wernike
- Institute of Diagnostic Virology, Friedrich-Loeffler-Institut, Südufer 10, 17493 Greifswald-Insel Riems, Germany
| | - Christine Klaus
- Institute for Bacterial Infections and Zoonoses, Friedrich-Loeffler-Institut, Naumburger Str. 96a, 07743 Jena, Germany
| | - Gerhard Dobler
- Bundeswehr Institute of Microbiology, German Center of Infection Research (DZIF) partner site Munich, Neuherbergstraße 11, 80937 München, Germany
| | - Martin Beer
- Institute of Diagnostic Virology, Friedrich-Loeffler-Institut, Südufer 10, 17493 Greifswald-Insel Riems, Germany.
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Rego ROM, Trentelman JJA, Anguita J, Nijhof AM, Sprong H, Klempa B, Hajdusek O, Tomás-Cortázar J, Azagi T, Strnad M, Knorr S, Sima R, Jalovecka M, Fumačová Havlíková S, Ličková M, Sláviková M, Kopacek P, Grubhoffer L, Hovius JW. Counterattacking the tick bite: towards a rational design of anti-tick vaccines targeting pathogen transmission. Parasit Vectors 2019; 12:229. [PMID: 31088506 PMCID: PMC6518728 DOI: 10.1186/s13071-019-3468-x] [Citation(s) in RCA: 72] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Accepted: 04/29/2019] [Indexed: 02/07/2023] Open
Abstract
Hematophagous arthropods are responsible for the transmission of a variety of pathogens that cause disease in humans and animals. Ticks of the Ixodes ricinus complex are vectors for some of the most frequently occurring human tick-borne diseases, particularly Lyme borreliosis and tick-borne encephalitis virus (TBEV). The search for vaccines against these diseases is ongoing. Efforts during the last few decades have primarily focused on understanding the biology of the transmitted viruses, bacteria and protozoans, with the goal of identifying targets for intervention. Successful vaccines have been developed against TBEV and Lyme borreliosis, although the latter is no longer available for humans. More recently, the focus of intervention has shifted back to where it was initially being studied which is the vector. State of the art technologies are being used for the identification of potential vaccine candidates for anti-tick vaccines that could be used either in humans or animals. The study of the interrelationship between ticks and the pathogens they transmit, including mechanisms of acquisition, persistence and transmission have come to the fore, as this knowledge may lead to the identification of critical elements of the pathogens' life-cycle that could be targeted by vaccines. Here, we review the status of our current knowledge on the triangular relationships between ticks, the pathogens they carry and the mammalian hosts, as well as methods that are being used to identify anti-tick vaccine candidates that can prevent the transmission of tick-borne pathogens.
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Affiliation(s)
- Ryan O. M. Rego
- Biology Centre, Institute of Parasitology, Czech Academy of Sciences, Branišovská 31, 37005 Ceske Budejovice, Czech Republic
| | - Jos J. A. Trentelman
- Amsterdam UMC, Location AMC, Center for Experimental and Molecular Medicine, Amsterdam, The Netherlands
| | - Juan Anguita
- CIC bioGUNE, 48160 Derio, Spain
- Ikerbasque, Basque Foundation for Science, 48012 Bilbao, Spain
| | - Ard M. Nijhof
- Institute for Parasitology and Tropical Veterinary Medicine, Freie Universität Berlin, Berlin, Germany
| | - Hein Sprong
- Centre for Zoonoses and Environmental Microbiology, Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
| | - Boris Klempa
- Institute of Virology, Biomedical Research Center of the Slovak Academy of Sciences, Bratislava, Slovakia
| | - Ondrej Hajdusek
- Biology Centre, Institute of Parasitology, Czech Academy of Sciences, Branišovská 31, 37005 Ceske Budejovice, Czech Republic
| | | | - Tal Azagi
- Centre for Zoonoses and Environmental Microbiology, Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
| | - Martin Strnad
- Biology Centre, Institute of Parasitology, Czech Academy of Sciences, Branišovská 31, 37005 Ceske Budejovice, Czech Republic
- Faculty of Science, University of South Bohemia, Branišovská 31, 37005 Ceske Budejovice, Czech Republic
| | - Sarah Knorr
- Institute for Parasitology and Tropical Veterinary Medicine, Freie Universität Berlin, Berlin, Germany
| | - Radek Sima
- Biology Centre, Institute of Parasitology, Czech Academy of Sciences, Branišovská 31, 37005 Ceske Budejovice, Czech Republic
| | - Marie Jalovecka
- Biology Centre, Institute of Parasitology, Czech Academy of Sciences, Branišovská 31, 37005 Ceske Budejovice, Czech Republic
- Faculty of Science, University of South Bohemia, Branišovská 31, 37005 Ceske Budejovice, Czech Republic
| | - Sabína Fumačová Havlíková
- Institute of Virology, Biomedical Research Center of the Slovak Academy of Sciences, Bratislava, Slovakia
| | - Martina Ličková
- Institute of Virology, Biomedical Research Center of the Slovak Academy of Sciences, Bratislava, Slovakia
| | - Monika Sláviková
- Institute of Virology, Biomedical Research Center of the Slovak Academy of Sciences, Bratislava, Slovakia
| | - Petr Kopacek
- Biology Centre, Institute of Parasitology, Czech Academy of Sciences, Branišovská 31, 37005 Ceske Budejovice, Czech Republic
- Faculty of Science, University of South Bohemia, Branišovská 31, 37005 Ceske Budejovice, Czech Republic
| | - Libor Grubhoffer
- Biology Centre, Institute of Parasitology, Czech Academy of Sciences, Branišovská 31, 37005 Ceske Budejovice, Czech Republic
- Faculty of Science, University of South Bohemia, Branišovská 31, 37005 Ceske Budejovice, Czech Republic
| | - Joppe W. Hovius
- Amsterdam UMC, Location AMC, Center for Experimental and Molecular Medicine, Amsterdam, The Netherlands
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Zhang Q, Li N, Deng C, Zhang Z, Li X, Yoshii K, Ye H, Zhang B. Trans Complementation of Replication-defective Omsk Hemorrhagic Fever Virus for Antiviral Study. Virol Sin 2019; 34:412-422. [PMID: 30949960 DOI: 10.1007/s12250-019-00109-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Accepted: 02/28/2019] [Indexed: 12/25/2022] Open
Abstract
Omsk hemorrhagic fever virus (OHFV) is a tick-borne flavivirus classified as a biosafety level-4 (BSL4) pathogen. Studies of OHFV are restricted to be conducted within BSL4 laboratories. Currently, no commercial vaccines or antiviral drugs are available against OHFV infection. In this study, we recovered a replication-deficient OHFV with an NS1 deletion (OHFV-ΔNS1) and reporter virus replacing NS1 with the Gaussia luciferase (Gluc) (OHFV-ΔNS1-Gluc). Both the defective OHFV-ΔNS1 and OHFV-ΔNS1-Gluc virus could only replicate efficiently in the BHK21 cell line expressing NS1 (BHK21NS1) but not in naïve BHK21 cells. The Gluc reporter gene of OHFV-ΔNS1-Gluc virus was maintained stably after serial passaging of BHK21NS1 cells and was used to surrogate the replication of OHFV. Using NITD008, OHFV-ΔNS1-Gluc virus was validated for antiviral screening, and high-throughput screening parameters were optimized in a 96-well plate format with a calculated Z' value above 0.5. The OHFV-ΔNS1-Gluc reporter virus is a powerful tool for antiviral screening as well as viral replication and pathogenesis studies in BSL2 laboratories.
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Affiliation(s)
- Qiuyan Zhang
- Key Laboratory of Special Pathogens and Biosafety, Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Na Li
- Key Laboratory of Special Pathogens and Biosafety, Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Chenglin Deng
- Key Laboratory of Special Pathogens and Biosafety, Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, China
| | - Zherui Zhang
- Key Laboratory of Special Pathogens and Biosafety, Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Xiaodan Li
- Key Laboratory of Special Pathogens and Biosafety, Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, China
| | - Kentaro Yoshii
- Laboratory of Public Health, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, 060-0818, Japan
| | - Hanqing Ye
- Key Laboratory of Special Pathogens and Biosafety, Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, China
| | - Bo Zhang
- Key Laboratory of Special Pathogens and Biosafety, Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, China.
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47
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Potokar M, Jorgačevski J, Zorec R. Astrocytes in Flavivirus Infections. Int J Mol Sci 2019; 20:ijms20030691. [PMID: 30736273 PMCID: PMC6386967 DOI: 10.3390/ijms20030691] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Revised: 01/27/2019] [Accepted: 01/29/2019] [Indexed: 12/14/2022] Open
Abstract
Virus infections of the central nervous system (CNS) can manifest in various forms of inflammation, including that of the brain (encephalitis) and spinal cord (myelitis), all of which may have long-lasting deleterious consequences. Although the knowledge of how different viruses affect neural cells is increasing, understanding of the mechanisms by which cells respond to neurotropic viruses remains fragmented. Several virus types have the ability to infect neural tissue, and astrocytes, an abundant and heterogeneous neuroglial cell type and a key element providing CNS homeostasis, are one of the first CNS cell types to get infected. Astrocytes are morphologically closely aligned with neuronal synapses, blood vessels, and ventricle cavities, and thereby have the capacity to functionally interact with neurons and endothelial cells. In this review, we focus on the responses of astrocytes to infection by neurotropic flaviviruses, including tick-borne encephalitis virus (TBEV), Zika virus (ZIKV), West Nile virus (WNV), and Japanese encephalitis virus (JEV), which have all been confirmed to infect astrocytes and cause multiple CNS defects. Understanding these mechanisms may help design new strategies to better contain and mitigate virus- and astrocyte-dependent neuroinflammation.
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Affiliation(s)
- Maja Potokar
- Laboratory of Neuroendocrinology-Molecular Cell Physiology, Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Zaloška 4, 1000 Ljubljana, Slovenia.
- Celica BIOMEDICAL, Tehnološki park 24, 1000 Ljubljana, Slovenia.
| | - Jernej Jorgačevski
- Laboratory of Neuroendocrinology-Molecular Cell Physiology, Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Zaloška 4, 1000 Ljubljana, Slovenia.
- Celica BIOMEDICAL, Tehnološki park 24, 1000 Ljubljana, Slovenia.
| | - Robert Zorec
- Laboratory of Neuroendocrinology-Molecular Cell Physiology, Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Zaloška 4, 1000 Ljubljana, Slovenia.
- Celica BIOMEDICAL, Tehnološki park 24, 1000 Ljubljana, Slovenia.
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Dissecting Flavivirus Biology in Salivary Gland Cultures from Fed and Unfed Ixodes scapularis (Black-Legged Tick). mBio 2019; 10:mBio.02628-18. [PMID: 30696737 PMCID: PMC6355982 DOI: 10.1128/mbio.02628-18] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Tick-borne flaviviruses (TBFVs) are responsible for more than 15,000 human disease cases each year, and Powassan virus lineage 2 (POWV-L2) deer tick virus has been a reemerging threat in North America over the past 20 years. Rapid transmission of TBFVs in particular emphasizes the importance of preventing tick bites, the difficulty in developing countermeasures to prevent transmission, and the importance of understanding TBFV infection in tick salivary glands (SGs). Tick blood feeding is responsible for phenomenal physiological changes and is associated with changes in TBFV multiplication within the tick and in SGs. Using SG cultures from Ixodes scapularis female ticks, the primary aims of this study were to identify cellular localization of virus-like particles in acini of infected SGs from fed and unfed ticks, localization of TBFV infection in infected SGs from fed ticks, and a tick transcript (with associated metabolic function) involved in POWV-L2 infection in SG cultures. The Ixodes scapularis tick transmits a number of pathogens, including tick-borne flaviviruses (TBFVs). In the United States, confirmed human infections with the Powassan virus (POWV) TBFV have a fatality rate of ∼10% and are increasing in incidence. Tick salivary glands (SGs) serve as an organ barrier to TBFV transmission, and little is known regarding the location of TBFV infection in SGs from fed ticks. Previous studies showed I. scapularis vanin (VNN) involved with TBFV infection of I. scapularis ISE6 embryonic cells, suggesting a potential role for this gene. The overall goal of this study was to use SG cultures to compare data on TBFV biology in SGs from fully engorged, replete (fed) ticks and from unfed ticks. TBFV multiplication was higher in SGs from fed ticks than in those from unfed ticks. Virus-like particles were observed only in granular acini of SGs from unfed ticks. The location of TBFV infection of SGs from fed ticks was observed in cells lining lobular ducts and trachea but not observed in acini. Transcript knockdown of VNN decreased POWV multiplication in infected SG cultures from both fed and unfed ticks. This work was the first to identify localization of TBFV multiplication in SG cultures from a fed tick and a tick transcript important for POWV multiplication in the tick SG, an organ critical for TBFV transmission. This research exemplifies the use of SG cultures in deciphering TBFV biology in the tick and as a translational tool for screening and identifying potential tick genes as potential countermeasure targets.
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Molecular detection of viruses causing hemorrhagic fevers in rodents in the south-west of Korea. J Neurovirol 2019; 25:239-247. [PMID: 30635845 DOI: 10.1007/s13365-018-0708-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Revised: 10/22/2018] [Accepted: 11/20/2018] [Indexed: 12/30/2022]
Abstract
Many pathogens causing hemorrhagic fevers of medical and veterinary importance have been identified and isolated from rodents in the Republic of Korea (ROK). We investigated the occurrence of emerging viruses causing hemorrhagic fevers, such as hemorrhagic fever with renal syndrome (HFRS), severe fever with thrombocytopenia syndrome (SFTS), and flaviviruses, from wild rodents. Striped field mice, Apodemus agrarius (n = 39), were captured during 2014-2015 in the south-west of ROK. Using molecular methods, lung samples were evaluated for SFTS virus, hantavirus, and flavivirus, and seropositivity was evaluated in the blood. A high positive rate of hantavirus (46.2%) was detected in A. agrarius lungs by reverse transcription-nested polymerase chain reaction (RT-N-PCR). The monthly occurrence of hantavirus was 16.7% in October, 86.7% in November, and 25% in August of the following year (p < 0.001). Moreover, 17.9% of blood samples were serologically positive for hantavirus antibodies. The most prevalent strain in A. agrarius was Hantaan virus. All samples were positive for neither SFTS virus nor flavivirus. Hantaan virus was detected in 86.7% of A. agrarius in November (autumn), and thus, virus shedding from A. agrarius can increase the risk of humans contracting HFRS. These findings may help to predict and prevent disease outbreaks in ROK.
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Abstract
The tick-borne pathogen Powassan virus is a rare cause of encephalitis in North America and the Russian Far East. The number of documented cases described since the discovery of Powassan virus in 1958 may be <150, although detection of cases has increased over the past decade. In the United States, the incidence of Powassan virus infections expanded from the estimated 1 case per year prior to 2005 to 10 cases per year during the subsequent decade. The increased detection rate may be associated with several factors, including enhanced surveillance, the availability of improved laboratory diagnostic methods, the expansion of the vector population, and, perhaps, altered human activities that lead to more exposure. Nonetheless, it remains unclear whether Powassan virus is indeed an emerging threat or if enzootic cycles in nature remain more-or-less stable with periodic fluctuations of host and vector population sizes. Despite the low disease incidence, the approximately 10% to 15% case fatality rate of neuroinvasive Powassan virus infection and the temporary or prolonged sequelae in >50% of survivors make Powassan virus a medical concern requiring the attention of public health authorities and clinicians. The medical importance of Powassan virus justifies more research on developing specific and effective treatments and prevention and control measures.
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Affiliation(s)
- Gábor Kemenesi
- Virological Research Group, Szentágothai Research Centre, University of Pécs, Pécs, Hungary
- Institute of Biology, Faculty of Sciences, University of Pécs, Pécs, Hungary
| | - Krisztián Bányai
- Institute for Veterinary Medical Research, Centre for Agricultural Research, Hungarian Academy of Sciences, Budapest, Hungary
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