Publications by authors named "Dániel Cadar"

82 Publications

Emerging Microbes & Infections - Original Article: Human Borna disease virus 1 (BoDV-1) encephalitis cases in the north and east of Germany.

Emerg Microbes Infect 2021 Nov 16:1-19. Epub 2021 Nov 16.

Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.

In 2021, three encephalitis cases due to the Borna disease virus 1 (BoDV-1) were diagnosed in the north and east of Germany. The patients were from the states of Thuringia, Saxony-Anhalt, and Lower Saxony. All were residents of known endemic areas for animal Borna disease but without prior diagnosed human cases. Except for one recently detected case in the state of Brandenburg, all >30 notified cases had occurred in, or were linked to, the southern state of Bavaria. Of the three detected cases described here, two infections were acute, while one infection was diagnosed retrospectively from archived brain autopsy tissue samples. One of the acute cases survived, but is permanently disabled. The cases were diagnosed by various techniques (serology, molecular assays, and immunohistology) following a validated testing scheme and adhering to a proposed case definition. Two cases were classified as confirmed BoDV-1 encephalitis, while one case was a probable infection with positive serology and typical brain magnetic resonance imaging, but without molecular confirmation. Of the three cases, one full virus genome sequence could be recovered. Our report highlights the need for awareness of a BoDV-1 etiology in cryptic encephalitis cases in all areas with known animal Borna disease endemicity in Europe, including virus-endemic regions in Austria, Liechtenstein, and Switzerland. BoDV-1 should be actively tested for in acute encephalitis cases with residence or rural exposure history in known Borna disease-endemic areas.
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http://dx.doi.org/10.1080/22221751.2021.2007737DOI Listing
November 2021

Genome Sequences of West Nile Virus Reference Materials.

Microbiol Resour Announc 2021 Oct 28;10(43):e0074021. Epub 2021 Oct 28.

Paul-Ehrlich-Institut, Langen, Germany.

We report the sequences of two West Nile virus (WNV) strains (lineages 1 and 2) developed by the Paul-Ehrlich-Institut as reference materials. The materials are calibrated against the 1 World Health Organization WNV RNA International Standard and are intended for use in nucleic acid technology assays supporting transfusion safety.
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http://dx.doi.org/10.1128/MRA.00740-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8552714PMC
October 2021

No Metagenomic Evidence of Causative Viral Pathogens in Postencephalitic Parkinsonism Following Encephalitis Lethargica.

Microorganisms 2021 Aug 12;9(8). Epub 2021 Aug 12.

Bernhard Nocht Institute for Tropical Medicine, 20359 Hamburg, Germany.

Postencephalitic parkinsonism (PEP) is a disease of unknown etiology and pathophysiology following encephalitis lethargica (EL), an acute-onset polioencephalitis of cryptic cause in the 1920s. PEP is a tauopathy with multisystem neuronal loss and gliosis, clinically characterized by bradykinesia, rigidity, rest tremor, and oculogyric crises. Though a viral cause of EL is likely, past polymerase chain reaction-based investigations in the etiology of both PEP and EL were negative. PEP might be caused directly by an unknown viral pathogen or the consequence of a post-infectious immunopathology. The development of metagenomic next-generation sequencing in conjunction with bioinformatic techniques has generated a broad-range tool for the detection of unknown pathogens in the recent past. Retrospective identification and characterization of pathogens responsible for past infectious diseases can be successfully performed with formalin-fixed paraffin-embedded (FFPE) tissue samples. In this study, we analyzed 24 FFPE brain samples from six patients with PEP by unbiased metagenomic next-generation sequencing. Our results show that no evidence for the presence of a specific or putative (novel) viral pathogen was found, suggesting a likely post-infectious immune-mediated etiology of PEP.
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http://dx.doi.org/10.3390/microorganisms9081716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8398509PMC
August 2021

Taxonomic update for mammalian anelloviruses (family Anelloviridae).

Arch Virol 2021 Oct;166(10):2943-2953

The Biodesign Center for Fundamental and Applied Microbiomics, Center for Evolution and Medicine, School of Life Sciences, Arizona State University, 1001 S. McAllister Ave, Tempe, AZ, 85287-5001, USA.

Anelloviruses are small negative-sense single-stranded DNA viruses with genomes ranging in size from 1.6 to 3.9 kb. The family Anelloviridae comprised 14 genera before the present changes. However, in the last five years, a large number of diverse anelloviruses have been identified in various organisms. Here, we undertake a global analysis of mammalian anelloviruses whose full genome sequences have been determined and have an intact open reading frame 1 (ORF1). We established new criteria for the classification of anelloviruses, and, based on our analyses, we establish new genera and species to accommodate the unclassified anelloviruses. We also note that based on the updated species demarcation criteria, some previously assigned species (n = 10) merge with other species. Given the rate at which virus sequence data are accumulating, and with the identification of diverse anelloviruses, we acknowledge that the taxonomy will have to be dynamic and continuously evolve to accommodate new members.
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http://dx.doi.org/10.1007/s00705-021-05192-xDOI Listing
October 2021

Taxonomic updates for the genus Gyrovirus (family Anelloviridae): recognition of several new members and establishment of species demarcation criteria.

Arch Virol 2021 Oct;166(10):2937-2942

The Biodesign Center for Fundamental and Applied Microbiomics, Center for Evolution and Medicine, School of Life Sciences, Arizona State University, 1001 S. McAllister Ave, Tempe, AZ, 85287-5001, USA.

The genus Gyrovirus was assigned to the family Anelloviridae in 2017 with only one recognized species, Chicken anemia virus. Over the last decade, many diverse viruses related to chicken anemia virus have been identified but not classified. Here, we provide a framework for the classification of new species in the genus Gyrovirus and communicate the establishment of nine new species. We adopted the 'Genus + freeform epithet' binomial system for the naming of these species.
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http://dx.doi.org/10.1007/s00705-021-05194-9DOI Listing
October 2021

Genomic and Micro-Evolutionary Features of (Variegated Squirrel Bornavirus 1, VSBV-1).

Microorganisms 2021 May 25;9(6). Epub 2021 May 25.

WHO Collaborating Centre for Arbovirus and Haemorrhagic Fever Reference and Research, Bernhard Nocht Institute for Tropical Medicine, 20359 Hamburg, Germany.

(VSBV-1) is an emerging zoonotic pathogen discovered in several exotic squirrel species and associated with fatal human encephalitis. The dynamics of VSBV-1 spread and evolution in its presumed natural hosts are unknown. Here, we present the phylogeny, micro-evolution, cross-species transmission and spread of VSBV-1 at a temporal and spatial resolution within the limits of animal husbandry. The results showed that VSBV-1 can be classified into six distinct groups and that the most recent common ancestor of the known German strains emerged at least 20 years ago. We here demonstrate that the genetic diversity of the VSBV-1 groups is shaped primarily by in situ evolution and most of the amino acid changes are deleterious polymorphisms removed by purifying selection. Evidence of adaptive evolution has been found in the G and L genes which might have an influence on transmission fitness. Furthermore, there was also evidence for some form of adaptive changes in the glycoprotein which suggests that many sites might be subjected to positive pressure evolving under episodic directional selection, indicating past occurrence of positive selection. Host switching events were detected as dominant evolutionary mechanisms driving the virus-host associations. Virus spread by animal trade followed by subsequent local micro-evolution in zoos and holdings is responsible for diversifying strains. Time-resolved phylogeny indicated that Prevost's squirrels might be the original squirrel species carrying and seeding the virus in Germany. This study provides the first insight into the ecology and micro-evolutionary dynamics of this novel viral pathogen in the captive exotic squirrel population under artificial ecological conditions (zoos and animal husbandry) and co-housing of different squirrel species.
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http://dx.doi.org/10.3390/microorganisms9061141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8227138PMC
May 2021

Active Case Finding of Current Bornavirus Infections in Human Encephalitis Cases of Unknown Etiology, Germany, 2018-2020.

Emerg Infect Dis 2021 05;27(5):1371-1379

Human bornavirus encephalitis is a severe and often fatal infection caused by variegated squirrel bornavirus 1 (VSBV-1) and Borna disease virus 1 (BoDV-1). We conducted a prospective study of bornavirus etiology of encephalitis cases in Germany during 2018-2020 by using a serologic testing scheme applied along proposed graded case definitions for VSBV-1, BoDV-1, and unspecified bornavirus encephalitis. Of 103 encephalitis cases of unknown etiology, 4 bornavirus infections were detected serologically. One chronic case was caused by VSBV-1 after occupational-related contact of a person with exotic squirrels, and 3 acute cases were caused by BoDV-1 in virus-endemic areas. All 4 case-patients died. Bornavirus etiology could be confirmed by molecular methods. Serologic testing for these cases was virus specific, discriminatory, and a practical diagnostic option for living patients if no brain tissue samples are available. This testing should be guided by clinical and epidemiologic suspicions, such as residence in virus-endemic areas and animal exposure.
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http://dx.doi.org/10.3201/eid2705.204490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084505PMC
May 2021

Metagenomic Snapshots of Viral Components in Guinean Bats.

Microorganisms 2021 Mar 15;9(3). Epub 2021 Mar 15.

WHO Collaborating Centre for Arbovirus and Haemorrhagic Fever Reference and Research, Bernhard Nocht Institute for Tropical Medicine, 20359 Hamburg, Germany.

To prevent the emergence of zoonotic infectious diseases and reduce their epidemic potential, we need to understand their origins in nature. Bats in the order Chiroptera are widely distributed worldwide and are natural reservoirs of prominent zoonotic viruses, including Nipah virus, Marburg virus, and possibly SARS-CoV-2. In this study, we applied unbiased metagenomic and metatranscriptomic approaches to decipher the virosphere of frugivorous and insectivorous bat species captured in Guéckédou, Guinea, the epicenter of the West African Ebola virus disease epidemic in 2013-2016. Our study provides a snapshot of the viral diversity present in these bat species, with several novel viruses reported for the first time in bats, as well as some bat viruses closely related to known human or animal pathogens. In addition, analysis of genomic DNA samples revealed the presence of an Ebola virus nucleoprotein (NP)-derived pseudogene inserted in its genome. These findings provide insight into the evolutionary traits of several virus families in bats and add evidence that nonretroviral integrated RNA viruses (NIRVs) derived from filoviruses may be common in bat genomes.
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http://dx.doi.org/10.3390/microorganisms9030599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999534PMC
March 2021

[West-Nile-Virus Infection acquired in Germany in a Kidney Transplant Recipient].

Dtsch Med Wochenschr 2021 04 29;146(7):482-486. Epub 2021 Mar 29.

Bernhard-Nocht-Institut für Tropenmedizin, Hamburg.

Background: West-Nile-Virus (WNV) is a widely distributed flavivirus that is mainly transmitted between birds through different mosquito species (e. g. Culex, Aedes), but may also be transmitted to mammals including humans. WNV causes a spectrum of disease, ranging from asymptomatic infection to encephalitis in a minority of cases. Risk factors for severe disease are older age, cardiovascular disease and an immunocompromised state.

Medical History And Clinical Examination: Here we report about a 60-year-old male patient who was referred to the University Hospital of Halle (Saale) with severe fever two years after kidney transplantation due to hypertensive nephropathy. No infection focus could be found and by day 6 in the course of his illness the patient developed neurologic symptoms and viral encephalitis was suspected.

Treatment And Course: The patient was initially treated with aciclovir. After initial reduction of immunosuppression, coincident graft dysfunction was treated with methylprednisolon. WNV-infection was suspected due to recent emerging human cases in the nearby area of the city of Leipzig. WNV lineage 2 was detected in the patient's urine by RT-PCR and seroconversion with presence of anti WNV IgM and IgG could be demonstrated. Consecutively, aciclovir treatment was stopped. The patient fully recovered and the transplanted kidney regained adequate function. Kidney biopsy did not reveal gross rejection of the transplant.

Conclusion: This case highlights the need to consider rarer causes of illness like WNV-infection particularly in risk groups for more severe outcomes of infectious disease. WNV may be detected by PCR in the blood and cerebrospinal fluid early in the course of infection but it is also excreted for a prolonged period of time in the urine. Seroconversion to anti WNV IgG and IgM may be shown but serologic cross-reactivity among members of the flaviviridae family must be considered.
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http://dx.doi.org/10.1055/a-1218-9096DOI Listing
April 2021

Introduction and spread of variegated squirrel bornavirus 1 (VSBV-1) between exotic squirrels and spill-over infections to humans in Germany.

Emerg Microbes Infect 2021 Dec;10(1):602-611

Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.

The variegated squirrel bornavirus 1 (VSBV-1) is a recently discovered emerging viral pathogen which causes severe and eventually fatal encephalitis in humans after contact to exotic squirrels in private holdings and zoological gardens. Understanding the VSBV-1 epidemiology is crucial to develop, implement, and maintain surveillance strategies for the detection and control of animal and human infections. Based on a newly detected human encephalitis case in a zoological garden, epidemiological squirrel trade investigations and molecular phylogeny analyses of VSBV-1 with temporal and spatial resolution were conducted. Phylogenetic analyses indicated a recent emergence of VSBV-1 in European squirrel holdings and several animal-animal and animal-human spill-over infections. Virus phylogeny linked to squirrel trade analysis showed the introduction of a common ancestor of the known current VSBV-1 isolates into captive exotic squirrels in Germany, most likely by Prevost's squirrels (). The links of the animal trade between private breeders and zoos, the likely introduction pathway of VSBV-1 into Germany, and the role of a primary animal distributor were elucidated. In addition, a seroprevalence study was performed among zoo animal caretakers from VSBV-1 affected zoos. No seropositive healthy zoo animal caretakers were found, underlining a probable high-case fatality rate of human VSBV-1 infections. This study illustrates the network and health consequences of uncontrolled wild pet trading as well as the benefits of molecular epidemiology for elucidation and future prevention of infection chains by zoonotic viruses. To respond to emerging zoonotic diseases rapidly, improved regulation and control strategies are urgently needed.
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http://dx.doi.org/10.1080/22221751.2021.1902752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018504PMC
December 2021

Phylogeny of Hungarian EBLV-1 strains using whole-genome sequence data.

Transbound Emerg Dis 2021 May 17;68(3):1323-1331. Epub 2020 Sep 17.

Institute for Veterinary Medical Research, Centre for Agricultural Research, Budapest, Hungary.

European bat lyssavirus 1 (EBLV-1) is a widespread lyssavirus across Europe, whose epizootic cycle is linked to a few bat species. Occasionally, EBLV-1 infection may occur in domestic animals and humans. EBLV-1 can be classified into two subtypes, where subtype EBLV-1a shows a wide geographic distribution between France and Russia whereas subtype EBLV-1b is distributed between Spain and Poland. In this study, we determined the genome sequence of two recent EBLV-1a strains detected in Hungary and analysed their adaptive evolution and phylodynamics. The data set that included 100 EBLV-1 genome sequences identified positive selection at selected sites in genes coding for viral proteins (N, codon 18; P, 141 and 155; G, 244 and 488; L, 168, 980, 1597 and 1754). A major genetic clade containing EBLV-1a isolates from Hungary, Slovakia, Denmark and Poland was estimated to have diverged during the 19th century whereas the divergence of the most recent ancestor of Hungarian and Slovakian isolates dates back to 1950 (time span, 1930 to 1970). Phylogeographic analysis of the EBLV-1a genomic sequences demonstrated strong evidence of viral dispersal from Poland to Hungary. This new information indicates that additional migratory flyways may help the virus spread, a finding that supplements the general theory on a west-to-east dispersal of EBLV-1a strains. Long-distance migrant bats may mediate the dispersal of EBLV-1 strains across Europe; however, structured surveillance and extended genome sequencing would be needed to better understand the epizootiology of EBLV-1 infections in Europe.
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http://dx.doi.org/10.1111/tbed.13789DOI Listing
May 2021

Discovery and genetic characterization of a novel orthonairovirus in Ixodes ricinus ticks from Danube Delta.

Infect Genet Evol 2021 03 5;88:104704. Epub 2021 Jan 5.

Bernhard Nocht Institute for Tropical Medicine, WHO Collaborating Centre for Arbovirus and Hemorrhagic Fever Reference and Research, 20359 Hamburg, Germany. Electronic address:

Different arthropod species are vectors of a wide array of arboviruses (arthropod-borne viruses) and have likely been central to viral evolution. To better understand the extent of arthropod-borne pathogens, as well as their origin and evolutionary history, it is crucial to uncover the full range of microbial agents, including viruses associated with arthropods. In this study, a collection of ticks obtained in 2016 directly from mammal and bird hosts from several rural and natural sites of Danube Delta was subjected to transcriptome sequencing and amplification assays. Vector surveillance revealed the presence of a novel orthonairovirus species, designated Sulina virus, in Ixodes ricinus ticks. Phylogenetic clustering of each viral protein consistently placed the new virus in the Orthonairovirus genus as a new genogroup closely related to Tamdy orthonairovirus, a genogroup comprising both pathogenic and tick-associated orthonairoviruses. The serological testing of engorged ticks and blood of infected hosts, along with the inoculation of vertebrate cells and mice found no specific antibodies or viral replication, suggesting that Sulina virus is an orthonairovirus associated with the virome of Ixodes ricinus. Finally, the characterization of a novel orthonairovirus identified using high throughput sequencing will advance our knowledge of interactions between viruses and tick vectors, expanding our perspective on fundamental questions regarding orthonairovirus evolution, diversity, ecology and potential of emergence as pathogens.
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http://dx.doi.org/10.1016/j.meegid.2021.104704DOI Listing
March 2021

Differential neurovirulence of Usutu virus lineages in mice and neuronal cells.

J Neuroinflammation 2021 Jan 6;18(1):11. Epub 2021 Jan 6.

Pathogenesis and Control of Chronic Infections, Université de Montpellier, INSERM, EFS, Montpellier, France.

Background: Usutu virus (USUV) is an emerging neurotropic arthropod-borne virus recently involved in massive die offs of wild birds predominantly reported in Europe. Although primarily asymptomatic or presenting mild clinical signs, humans infected by USUV can develop neuroinvasive pathologies (including encephalitis and meningoencephalitis). Similar to other flaviviruses, such as West Nile virus, USUV is capable of reaching the central nervous system. However, the neuropathogenesis of USUV is still poorly understood, and the virulence of the specific USUV lineages is currently unknown. One of the major complexities of the study of USUV pathogenesis is the presence of a great diversity of lineages circulating at the same time and in the same location.

Methods: The aim of this work was to determine the neurovirulence of isolates from the six main lineages circulating in Europe using mouse model and several neuronal cell lines (neurons, microglia, pericytes, brain endothelial cells, astrocytes, and in vitro Blood-Brain Barrier model).

Results: Our results indicate that all strains are neurotropic but have different virulence profiles. The Europe 2 strain, previously described as being involved in several clinical cases, induced the shortest survival time and highest mortality in vivo and appeared to be more virulent and persistent in microglial, astrocytes, and brain endothelial cells, while also inducing an atypical cytopathic effect. Moreover, an amino acid substitution (D3425E) was specifically identified in the RNA-dependent RNA polymerase domain of the NS5 protein of this lineage.

Conclusions: Altogether, these data show a broad neurotropism for USUV in the central nervous system with lineage-dependent virulence. Our results will help to better understand the biological and epidemiological diversity of USUV infection.
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http://dx.doi.org/10.1186/s12974-020-02060-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789689PMC
January 2021

Comparative Metagenomics of Palearctic and Neotropical Avian Cloacal Viromes Reveal Geographic Bias in Virus Discovery.

Microorganisms 2020 Nov 26;8(12). Epub 2020 Nov 26.

Department of Genetics, Physiology and Microbiology, Faculty of Biology, Complutense University of Madrid, José Antonio Novais, 12, 28040 Madrid, Spain.

Our understanding about viruses carried by wild animals is still scarce. The viral diversity of wildlife may be best described with discovery-driven approaches to the study of viral diversity that broaden research efforts towards non-canonical hosts and remote geographic regions. Birds have been key organisms in the transmission of viruses causing important diseases, and wild birds are threatened by viral spillovers associated with human activities. However, our knowledge of the avian virome may be biased towards poultry and highly pathogenic diseases. We describe and compare the fecal virome of two passerine-dominated bird assemblages sampled in a remote Neotropical rainforest in French Guiana (Nouragues Natural Reserve) and a Mediterranean forest in central Spain (La Herrería). We used metagenomic data to quantify the degree of functional and genetic novelty of viruses recovered by examining if the similarity of the contigs we obtained to reference sequences differed between both locations. In general, contigs from Nouragues were significantly less similar to viruses in databases than contigs from La Herrería using Blastn but not for Blastx, suggesting that pristine regions harbor a yet unknown viral diversity with genetically more singular viruses than more studied areas. Additionally, we describe putative novel viruses of the families , and . These results highlight the importance of wild animals and remote regions as sources of novel viruses that substantially broaden the current knowledge of the global diversity of viruses.
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http://dx.doi.org/10.3390/microorganisms8121869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761369PMC
November 2020

Lassa fever in Benin: description of the 2014 and 2016 epidemics and genetic characterization of a new Lassa virus.

Emerg Microbes Infect 2020 Dec;9(1):1761-1770

Virology Department, Bernhard-Nocht Institute for Tropical Medicine, Hamburg, Germany.

We report two outbreaks of Lassa fever that occurred in Benin in 2014 and 2016 with 20 confirmed cases and 50% (10/20) mortality. Benin was not previously considered to be an endemic country for Lassa fever, resulting in a delay to diagnose the disease and its human transmission. Molecular investigations showed the viral genomes to be similar to that of the Togo strain, which is genetically very different from other known strains and confirms the existence of a new lineage. Endemic circulation of Lassa virus in a new territory and the genetic diversity thus confirm that this virus represents a growing threat for West African people. Given the divergence of the Benin strain from the prototypic Josiah Sierra Leone strain frequently used to generate vaccine candidates, the efficacy of vaccine candidates should also be demonstrated with this strain.
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http://dx.doi.org/10.1080/22221751.2020.1796528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473144PMC
December 2020

Severe Multiorgan Failure Following Yellow Fever Vaccination.

Vaccines (Basel) 2020 May 26;8(2). Epub 2020 May 26.

Center for Infectious Diseases, Virology, University Hospital of Heidelberg, 69120 Heidelberg, Germany.

Background: The yellow fever (YF) vaccination is recommended by the WHO for people traveling or living in endemic areas at risk for yellow fever infections in Africa and South America. Although the live attenuated yellow fever vaccine is a safe and efficient vaccine, rare serious adverse events after vaccination have been reported.

Case Presentation: We present the case of a 74-year-old male with multiorgan failure after yellow fever vaccination for a trip to Brazil. The patient required admission to the intensive care unit with a prolonged stay due to severe organ dysfunction. Five days after the YF vaccination, the patient experienced nausea, vomiting, diarrhea, and general illness. Three days later he sought medical attention and was transferred to the University Hospital Heidelberg with beginning multiorgan failure and severe septic shock, including hypotonia, tachypnea, thrombopenia, and acute renal failure the same day. Within one week after vaccination, antibodies against YF virus were already detectable and progressively increased over the next two weeks. Viral RNA was detected in serum on the day of admission, with a viral load of 1.0 × 10 copies/mL. The YF virus (YFV) RNA was also present in tracheal secretions for several weeks and could be detected in urine samples up to 20 weeks after vaccination, with a peak viral load of 1.3 × 10 copies/mL. After 20 weeks in the ICU with nine weeks of mechanical ventilation, the patient was transferred to another hospital for further recovery.

Conclusions: The risk for severe adverse events due to the YF vaccination should be balanced against the risk of acquiring a severe YF infection, especially in elderly travelers.
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http://dx.doi.org/10.3390/vaccines8020249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349955PMC
May 2020

West Nile Virus Epidemic in Germany Triggered by Epizootic Emergence, 2019.

Viruses 2020 04 15;12(4). Epub 2020 Apr 15.

Bernhard Nocht Institute for Tropical Medicine, WHO Collaborating Centre for Arbovirus and Hemorrhagic Fever Reference and Research, 20359 Hamburg, Germany.

One year after the first autochthonous transmission of West Nile virus (WNV) to birds and horses in Germany, an epizootic emergence of WNV was again observed in 2019. The number of infected birds and horses was considerably higher compared to 2018 (12 birds, two horses), resulting in the observation of the first WNV epidemy in Germany: 76 cases in birds, 36 in horses and five confirmed mosquito-borne, autochthonous human cases. We demonstrated that Germany experienced several WNV introduction events and that strains of a distinct group (Eastern German WNV clade), which was introduced to Germany as a single introduction event, dominated mosquito, birds, horse and human-related virus variants in 2018 and 2019. Virus strains in this clade are characterized by a specific-Lys2114Arg mutation, which might lead to an increase in viral fitness. Extraordinary high temperatures in 2018/2019 allowed a low extrinsic incubation period (EIP), which drove the epizootic emergence and, in the end, most likely triggered the 2019 epidemic. Spatiotemporal EIP values correlated with the geographical WNV incidence. This study highlights the risk of a further spread in Germany in the next years with additional human WNV infections. Thus, surveillance of birds is essential to provide an early epidemic warning and thus, initiate targeted control measures.
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http://dx.doi.org/10.3390/v12040448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7232143PMC
April 2020

Letea Virus: Comparative Genomics and Phylogenetic Analysis of a Novel Reassortant Orbivirus Discovered in Grass Snakes ().

Viruses 2020 02 21;12(2). Epub 2020 Feb 21.

Bernhard Nocht Institute for Tropical Medicine, WHO Collaborating Centre for Arbovirus and Hemorrhagic Fever Reference and Research, 20359 Hamburg, Germany.

The discovery and characterization of novel arthropod-borne viruses provide valuable information on their genetic diversity, ecology, evolution and potential to threaten animal or public health. Arbovirus surveillance is not conducted regularly in Romania, being particularly very scarce in the remote and diverse areas like the Danube Delta. Here we describe the detection and genetic characterization of a novel orbivirus (: ) designated as Letea virus, which was found in grass snakes () during a metagenomic and metatranscriptomic survey conducted between 2014 and 2017. This virus is the first orbivirus discovered in reptiles. Phylogenetic analyses placed Letea virus as a highly divergent species in the -/sand fly-borne orbivirus clade. Gene reassortment and intragenic recombination were detected in the majority of the nine Letea virus strains obtained, implying that these mechanisms play important roles in the evolution and diversification of the virus. However, the screening of arthropods, including biting midges collected within the same surveillance program, tested negative for Letea virus infection and could not confirm the arthropod vector of the virus. The study provided complete genome sequences for nine Letea virus strains and new information about orbivirus diversity, host range, ecology and evolution. The phylogenetic associations warrant further screening of arthropods, as well as sustained surveillance efforts for elucidation of Letea virus natural cycle and possible implications for animal and human health.
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http://dx.doi.org/10.3390/v12020243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7077223PMC
February 2020

Blood-meal analysis of Culicoides (Diptera: Ceratopogonidae) reveals a broad host range and new species records for Romania.

Parasit Vectors 2020 Feb 17;13(1):79. Epub 2020 Feb 17.

WHO Collaborating Centre for Arbovirus and Hemorrhagic Fever Reference and Research, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.

Background: Culicoides biting midges are potential vectors of different pathogens. However, especially for eastern Europe, there is a lack of knowledge on the host-feeding patterns of this vector group. Therefore, this study aimed to identify Culicoides spp. and their vertebrate hosts collected in a wetland ecosystem.

Methods: Culicoides spp. were collected weekly from May to August 2017, using Biogents traps with UV light at four sites in the Danube Delta Biosphere Reserve, Romania. Vectors and hosts were identified with a DNA barcoding approach. The mitochondrial cytochrome c oxidase subunit 1 was used to identify Culicoides spp., while vertebrate hosts were determined targeting cytochrome b or 16S rRNA gene fragments. A maximum likelihood phylogenetic tree was constructed to verify the biting midge identity against other conspecific Palaearctic Culicoides species. A set of unfed midges was used for morphological confirmation of species identification using slide-mounted wings.

Results: Barcoding allowed the species identification and detection of corresponding hosts for 1040 (82.3%) of the 1264 analysed specimens. Eight Culicoides spp. were identified with Culicoides griseidorsum, Culicoides puncticollis and Culicoides submaritimus as new species records for Romania. For 39 specimens no similar sequences were found in GenBank. This group of unknown Culicoides showed a divergence of 15.6-16.3% from the closest identified species and clustered in a monophyletic clade, i.e. a novel species or a species without reference sequences in molecular libraries. For all Culicoides spp., nine mammalian and 24 avian species were detected as hosts. With the exception of C. riethi (n = 12), at least one avian host was detected for all Culicoides spp., but this host group only dominated for Culicoides kibunensis and the unknown Culicoides sp.. The most common host group were mammals (n = 993, 87.6% of all identified blood sources) dominated by cattle (n = 817, 70.6%).

Conclusions: Most Culicoides spp. showed a broad host-feeding pattern making them potential bridge vectors. At the same time, new records of biting midge species for Romania, as well as a potentially unknown Culicoides species, highlight the lack of knowledge regarding the biting midge species and their genetic diversity in eastern Europe.
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http://dx.doi.org/10.1186/s13071-020-3938-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7027113PMC
February 2020

On detection thresholds-a review on diagnostic approaches in the infectious disease laboratory and the interpretation of their results.

Acta Trop 2020 May 30;205:105377. Epub 2020 Jan 30.

Institute for Medical Microbiology, Virology and Hygiene, University Medicine Rostock, Rostock, Germany; Department of Microbiology and Hospital Hygiene, Bundeswehr Hospital Hamburg, Hamburg, Germany. Electronic address:

Diagnostic testing in the infectious disease laboratory facilitates decision-making by physicians at the bedside as well as epidemiological assessments and surveillance at study level. Problems may arise if test results are uncritically considered as being the same as the unknown true value. To allow a better understanding, the influence of external factors on the interpretation of test results is introduced with the example of prevalence, followed by the presentation of strengths and weaknesses of important techniques in the infectious disease laboratory like microscopy, cultural diagnostics, serology, mass spectrometry, nucleic acid amplification and hypothesis-free metagenomic sequencing with focus on basic, high-technology and potential future approaches. Special problems like multiplex testing as well as uncertainty of test evaluations, if no gold standard is available, are also stressed with a final glimpse on emerging future technologies for the infectious disease laboratory. In the conclusions, suitability for point-of-care-testing and field laboratory applications is summarized. The aim is to illustrate the limitations of diagnostic accuracy to both clinicians and study planners and to stress the importance of close cooperation with experts in laboratory disciplines so as to avoid potentially critical misunderstandings due to inappropriate interpretation of diagnostic test results.
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http://dx.doi.org/10.1016/j.actatropica.2020.105377DOI Listing
May 2020

Ecology of West Nile Virus in the Danube Delta, Romania: Phylogeography, Xenosurveillance and Mosquito Host-Feeding Patterns.

Viruses 2019 12 14;11(12). Epub 2019 Dec 14.

Bernhard Nocht Institute for Tropical Medicine, WHO Collaborating Centre for Arbovirus and Hemorrhagic Fever Reference and Research, 20359 Hamburg, Germany.

The ecology of West Nile virus (WNV) in the Danube Delta Biosphere Reserve (Romania) was investigated by combining studies on the virus genetics, phylogeography, xenosurveillance and host-feeding patterns of mosquitoes. Between 2014 and 2016, 655,667 unfed and 3842 engorged mosquito females were collected from four sampling sites. Blood-fed mosquitoes were negative for WNV-RNA, but two pools of unfed s.l./ collected in 2014 were tested positive. Our results suggest that Romania experienced at least two separate WNV lineage 2 introductions: from Africa into Danube Delta and from Greece into south-eastern Romania in the 1990s and early 2000s, respectively. The genetic diversity of WNV in Romania is primarily shaped by in situ evolution. WNV-specific antibodies were detected for 19 blood-meals from dogs and horses, but not from birds or humans. The hosts of mosquitoes were dominated by non-human mammals (19 species), followed by human and birds (23 species). Thereby, the catholic host-feeding pattern of s.l./ with a relatively high proportion of birds indicates the species' importance as a potential bridge vector. The low virus prevalence in combination with WNV-specific antibodies indicate continuous, but low activity of WNV in the Danube Delta during the study period.
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http://dx.doi.org/10.3390/v11121159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6950446PMC
December 2019

A Novel and Divergent Gyrovirus with Unusual Genomic Features Detected in Wild Passerine Birds from a Remote Rainforest in French Guiana.

Viruses 2019 12 11;11(12). Epub 2019 Dec 11.

Department of Genetics, Physiology and Microbiology, Complutense University of Madrid, Calle José Antonio Novais 12, 28040 Madrid, Spain.

Sequence-independent amplification techniques have become important tools for virus discovery, metagenomics, and exploration of viral diversity at the global scale, especially in remote areas. Here, we describe the detection and genetic characterization of a novel gyrovirus, named GyV11, present in cloacal, oral, and blood samples from neotropical wild birds in French Guiana. The molecular epidemiology revealed the presence of GyV11 only in passerine birds from three different species at a low prevalence (0.73%). This is the first characterization and prevalence study of a gyrovirus carried out in resident wild bird populations in a remote region, and provides evidence of the fecal-oral route transmission and local circulation of the virus. The molecular phylogeny of gyroviruses reveals the existence of two distinct gyrovirus lineages in which GyV11 is phylogenetically distinct from previously reported gyroviruses. Furthermore, GyV11 is placed basal in the gyrovirus phylogeny, likely owing to its ancestral origin and marked divergence. This study also provides important insights into the ecology, epidemiology, and genomic features of gyroviruses in a remote neotropical rainforest. The pathogenesis of this virus in avian species or whether GyV11 can infect humans and/or chickens needs to be further investigated.
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http://dx.doi.org/10.3390/v11121148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6950609PMC
December 2019

Usutu Virus Epizootic in Belgium in 2017 and 2018: Evidence of Virus Endemization and Ongoing Introduction Events.

Vector Borne Zoonotic Dis 2020 01 3;20(1):43-50. Epub 2019 Sep 3.

Fundamental and Applied Research for Animals & Health (FARAH), Faculty of Veterinary Medicine, University of Liège, Liège, Belgium.

Wildlife surveillance allowed the monitoring of the zoonotic mosquito-borne Usutu virus (USUV) in birds and bats () in southern Belgium in 2017 and 2018. USUV-RNA was detected in 69 birds (of 253) from 15 species, among which 7 species had not previously been reported to be susceptible to the infection. Similarly, 2 bats (of 10) were detected positive by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR). USUV-associated lesions were mainly found in Eurasian Blackbirds (), in which USUV antigens were demonstrated by immunohistochemistry in the brain, heart, liver, kidney, intestine, and lung. Partial nonstructural protein 5 gene-based phylogenetic analysis showed several identical or closely related strains from 2016, 2017, and 2018 clustering together within Europe 3 or Africa 3 lineages. Further, one USUV strain detected in a common chaffinch () manifested a close genetic relationship with the European 1 strains circulating in Hungary and Austria. Our data provide evidence of USUV endemization in southern Belgium in local birds and bats, extension of the host range of the virus and ongoing virus introduction from abroad, likely by migratory birds. Our results highlight the need for vigilance in the forthcoming years toward new virus-associated outbreaks in birds and possible human infections in Belgium.
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http://dx.doi.org/10.1089/vbz.2019.2469DOI Listing
January 2020

Phylogeography of Lassa Virus in Nigeria.

J Virol 2019 11 15;93(21). Epub 2019 Oct 15.

Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.

Lassa virus is genetically diverse with several lineages circulating in West Africa. This study aimed at describing the sequence variability of Lassa virus across Nigeria and inferring its spatiotemporal evolution. We sequenced and isolated 77 Lassa virus strains from 16 Nigerian states. The final data set, including previous works, comprised metadata and sequences of 219 unique strains sampled between 1969 and 2018 in 22 states. Most of this data originated from Lassa fever patients diagnosed at Irrua Specialist Teaching Hospital, Edo State, Nigeria. The majority of sequences clustered with the main Nigerian lineages II and III, while a few sequences formed a new cluster related to Lassa virus strains from Within lineages II and III, seven and five sublineages, respectively, were distinguishable. Phylogeographic analysis suggests an origin of lineage II in the southeastern part of the country around Ebonyi State and a main vector of dispersal toward the west across the Niger River, through Anambra, Kogi, Delta, and Edo into Ondo State. The frontline of virus dispersal appears to be in Ondo. Minor vectors are directed northeast toward Taraba and Adamawa and south toward Imo and Rivers. Lineage III might have spread from northern Plateau State into Kaduna, Nasarawa, Federal Capital Territory, and Bauchi. One sublineage moved south and crossed the Benue River into Benue State. This study provides a geographic mapping of lineages and phylogenetic clusters in Nigeria at a higher resolution. In addition, we estimated the direction and time frame of virus dispersal in the country. Lassa virus is the causative agent of Lassa fever, a viral hemorrhagic fever with a case fatality rate of approximately 30% in Africa. Previous studies disclosed a geographical pattern in the distribution of Lassa virus strains and a westward movement of the virus across West Africa during evolution. Our study provides a deeper understanding of the geography of genetic lineages and sublineages of the virus in Nigeria. In addition, we modeled how the virus spread in the country. This knowledge allows us to predict into which geographical areas the virus might spread in the future and prioritize areas for Lassa fever surveillance. Our study not only aimed to generate Lassa virus sequences from across Nigeria but also to isolate and conserve the respective viruses for future research. Both isolates and sequences are important for the development and evaluation of medical countermeasures to treat and prevent Lassa fever, such as diagnostics, therapeutics, and vaccines.
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http://dx.doi.org/10.1128/JVI.00929-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6803284PMC
November 2019

A novel group of avian astroviruses from Neotropical passerine birds broaden the diversity and host range of Astroviridae.

Sci Rep 2019 07 2;9(1):9513. Epub 2019 Jul 2.

Department of Genetics, Physiology and Microbiology, Faculty of Biology, Complutense University of Madrid, José Antonio Novais, 12, 28040, Madrid, Spain.

Metagenomics is helping to expand the known diversity of viruses, especially of those with poorly studied hosts in remote areas. The Neotropical region harbors a considerable diversity of avian species that may play a role as both host and short-distance vectors of unknown viruses. Viral metagenomics of cloacal swabs from 50 Neotropical birds collected in French Guiana revealed the presence of four complete astrovirus genomes. They constitute an early diverging novel monophyletic clade within the Avastrovirus phylogeny, representing a putative new astrovirus species (provisionally designated as Avastrovirus 5) according to the International Committee on Taxonomy of Viruses (ICTV) classification criteria. Their genomic organization shares some characteristics with Avastrovirus but also with Mamastrovirus. The pan-astrovirus RT-PCR analysis of the cloacal samples of 406 wild Neotropical birds showed a community-level prevalence of 4.9% (5.1% in passerines, the highest described so far in this order of birds). By screening birds of a remote region, we expanded the known host range of astroviruses to the avian families Cardinalidae, Conopophagidae, Furnariidae, Thamnophilidae, Turdidae and Tyrannidae. Our results provide important first insights into the unexplored viral communities, the ecology, epidemiology and features of host-pathogen interactions that shape the evolution of avastroviruses in a remote Neotropical rainforest.
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http://dx.doi.org/10.1038/s41598-019-45889-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6606752PMC
July 2019

Viral metagenomics revealed novel betatorquevirus species in pediatric inpatients with encephalitis/meningoencephalitis from Ghana.

Sci Rep 2019 02 20;9(1):2360. Epub 2019 Feb 20.

German Center for Infection Research, Hamburg-Borstel-Lübeck-Riems, Borstel, 20359, Germany.

The cause of acute encephalitis/meningoencephalitis in pediatric patients remains often unexplained despite extensive investigations for large panel of pathogens. To explore a possible viral implication, we investigated the virome of cerebrospinal fluid specimens of 70 febrile pediatric inpatients with clinical compatible encephalitis/meningoencephalitis. Using viral metagenomics, we detected and genetically characterized three novel human Torque teno mini virus (TTMV) species (TTMV-G1-3). Phylogenetically, TTMV-G1-3 clustered in three novel monophyletic lineages within genus Betatorquevirus of the Anelloviridae family. TTMV-G1-3 were highly prevalent in diseased children, but absent in the healthy cohort which may indicate an association of TTMV species with febrile illness. With 2/3 detected malaria co-infection, it remains unclear if these novel anellovirus species are causative agents or increase disease severity by interaction with malaria parasites. The presence of the viruses 28 days after initiating antimalarial and/or antibiotic treatment suggests a still active viral infection likely as effect of parasitic and/or bacterial co-infection that may have initiated a modulated immune system environment for viral replication or a defective virus clearance. This study increases the current knowledge on the genetic diversity of TTMV and strengthens that human anelloviruses can be considered as biomarkers for strong perturbations of the immune system in certain pathological conditions.
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http://dx.doi.org/10.1038/s41598-019-38975-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6382885PMC
February 2019

West Nile virus epizootic in Germany, 2018.

Antiviral Res 2019 02 11;162:39-43. Epub 2018 Dec 11.

Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Institute of Novel and Emerging Infectious Diseases, Greifswald-Insel Riems, Germany; German Centre for Infection Research (DZIF), Partner Site Hamburg-Luebeck-Borstel, Greifswald-Insel Riems, Germany. Electronic address:

The summer of 2018 in Germany was the second hottest and driest on record. These generally extremely favorable climatic conditions most likely triggered the further expansion and the efficient propagation of the zoonotic arthropod-borne West Nile virus in many Southern/Southeastern and even Central European countries. WNV infections were detected for the first time in resident wild and aviary birds, such as common blackbirds, northern goshawks and great grey owls in Eastern and Southeastern Germany. The causative WNV strain belonged to the central European subclade II. Phylogeographic analysis indicated a single introduction event of WNV into Germany, most likely in 2016 from Czech Republic, and also a unique non-synonymous mutation in the NS3 gene. Extraordinary high temperatures in 2018 presumably led to decreased averaged extrinsic incubation period values for WNV in mosquitoes, leading to rapid virus amplification and greater transmission risk for vertebrates in Germany. Blood transfusion services and clinicians in Germany should be aware of these possible WNV infection risks in humans especially during late summer.
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http://dx.doi.org/10.1016/j.antiviral.2018.12.005DOI Listing
February 2019

Dengue Virus IgM Serotyping by ELISA with Recombinant Mutant Envelope Proteins.

Emerg Infect Dis 2019 01 17;25(1):1111-1115. Epub 2019 Jan 17.

We developed an IgM-based ELISA that identifies the dengue virus serotype of recent infections. Dominant serotypes were detectable in 91.1% of samples from travelers and 86.5% of samples from residents of endemic regions; 97.1% corresponded to the serotype identified by PCR. This ELISA enables more accurate reporting of epidemiologic findings.
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http://dx.doi.org/10.3201/eid2501.180605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6302594PMC
January 2019

Male offspring born to mildly ZIKV-infected mice are at risk of developing neurocognitive disorders in adulthood.

Nat Microbiol 2018 10 10;3(10):1161-1174. Epub 2018 Sep 10.

Institute for Clinical and Laboratory Chemistry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Congenital Zika virus (ZIKV) syndrome may cause fetal microcephaly in ~1% of affected newborns. Here, we investigate whether the majority of clinically inapparent newborns might suffer from long-term health impairments not readily visible at birth. Infection of immunocompetent pregnant mice with high-dose ZIKV caused severe offspring phenotypes, such as fetal death, as expected. By contrast, low-dose (LD) maternal ZIKV infection resulted in reduced fetal birth weight but no other obvious phenotypes. Male offspring born to LD ZIKV-infected mothers had increased testosterone (TST) levels and were less likely to survive in utero infection compared to their female littermates. Males also presented an increased number of immature neurons in apical and basal hippocampal dendrites, while female offspring had immature neurons in basal dendrites only. Moreover, male offspring with high but not very high (storm) TST levels were more likely to suffer from learning and memory impairments compared to females. Future studies are required to understand the impact of TST on neuropathological and neurocognitive impairments in later life. In summary, increased sex-specific vigilance is required in countries with high ZIKV prevalence, where impaired neurodevelopment may be camouflaged by a healthy appearance at birth.
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http://dx.doi.org/10.1038/s41564-018-0236-1DOI Listing
October 2018
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