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2.  Bioinformatics in New Generation Flavivirus Vaccines 
Flavivirus infections are the most prevalent arthropod-borne infections world wide, often causing severe disease especially among children, the elderly, and the immunocompromised. In the absence of effective antiviral treatment, prevention through vaccination would greatly reduce morbidity and mortality associated with flavivirus infections. Despite the success of the empirically developed vaccines against yellow fever virus, Japanese encephalitis virus and tick-borne encephalitis virus, there is an increasing need for a more rational design and development of safe and effective vaccines. Several bioinformatic tools are available to support such rational vaccine design. In doing so, several parameters have to be taken into account, such as safety for the target population, overall immunogenicity of the candidate vaccine, and efficacy and longevity of the immune responses triggered. Examples of how bio-informatics is applied to assist in the rational design and improvements of vaccines, particularly flavivirus vaccines, are presented and discussed.
doi:10.1155/2010/864029
PMCID: PMC2867002  PMID: 20467477
3.  In Vitro Assessment of the Immunological Significance of a Human Monoclonal Antibody Directed to the Influenza A Virus Nucleoprotein 
Influenza A viruses cause annual epidemics and occasionally pandemics. Antibodies directed to the conserved viral nucleoprotein (NP) may play a role in immunity against various influenza A virus subtypes. Here, we assessed the immunological significance of a human monoclonal antibody directed to NP in vitro. This antibody bound to virus-infected cells but did not display virus-neutralizing activity, complement-dependent cell cytotoxicity, or opsonization of viral antigen for improved antigen presentation to CD8+ T cells by dendritic cells.
doi:10.1128/CVI.00339-13
PMCID: PMC3754521  PMID: 23761662
4.  Cowpox Virus Transmission from Rats to Monkeys, the Netherlands 
Emerging Infectious Diseases  2006;12(6):1005-1007.
We report an outbreak of cowpox virus among monkeys at a sanctuary for exotic animals. Serologic analysis and polymerase chain reaction were performed on blood and swab samples from different rodent species trapped at the sanctuary during the outbreak. Sequence comparison and serologic results showed that brown rats (Rattus norvegicus) transmitted the virus to monkeys.
doi:10.3201/eid1206.051513
PMCID: PMC3373046  PMID: 16707063
Poxvirus; zoonosis; nonhuman primates; transmission; rodents; dispatch
5.  Nonhuman Primate Models for SARS 
PLoS Medicine  2006;3(5):e194.
Osterhaus and Haagmans discuss a new study in PLoS Medicine that supports the use of the cynomolgus macaque model to study SARS pathogenesis and to test intervention strategies.
doi:10.1371/journal.pmed.0030194
PMCID: PMC1435785  PMID: 16608385
6.  Identification of Multiple Novel Viruses, Including a Parvovirus and a Hepevirus, in Feces of Red Foxes 
Journal of Virology  2013;87(13):7758-7764.
Red foxes (Vulpes vulpes) are the most widespread members of the order of Carnivora. Since they often live in (peri)urban areas, they are a potential reservoir of viruses that transmit from wildlife to humans or domestic animals. Here we evaluated the fecal viral microbiome of 13 red foxes by random PCR in combination with next-generation sequencing. Various novel viruses, including a parvovirus, bocavirus, adeno-associated virus, hepevirus, astroviruses, and picobirnaviruses, were identified.
doi:10.1128/JVI.00568-13
PMCID: PMC3700315  PMID: 23616657
7.  Epidemiology of Influenza A Virus among Black-headed Gulls, the Netherlands, 2006–2010 
Emerging Infectious Diseases  2014;20(1):138-141.
We sampled 7,511 black-headed gulls for influenza virus in the Netherlands during 2006–2010 and found that subtypes H13 and H16 caused annual epidemics in fledglings on colony sites. Our findings validate targeted surveillance of wild waterbirds and clarify underlying factors for influenza virus emergence in other species.
doi:10.3201/eid2001.130984
PMCID: PMC3884729  PMID: 24377955
influenza A virus; viruses; influenza; avian influenza; Charadriiformes; epidemics; virulence; disease reservoirs; zoonoses; black-headed gulls; the Netherlands
8.  Measles Virus Infection of Epithelial Cells in the Macaque Upper Respiratory Tract Is Mediated by Subepithelial Immune Cells 
Journal of Virology  2013;87(7):4033-4042.
Measles virus (MV), one of the most contagious viruses infecting humans, causes a systemic infection leading to fever, immune suppression, and a characteristic maculopapular rash. However, the specific mechanism or mechanisms responsible for the spread of MV into the respiratory epithelium in the late stages of the disease are unknown. Here we show the crucial role of PVRL4 in mediating the spread of MV from immune to epithelial cells by generating a PVRL4 “blind” recombinant wild-type MV and developing a novel in vitro coculture model of B cells with primary differentiated normal human bronchial epithelial cells. We utilized the macaque model of measles to analyze virus distribution in the respiratory tract prior to and at the peak of MV replication. Expression of PVRL4 was widespread in both the lower and upper respiratory tract (URT) of macaques, indicating MV transmission can be facilitated by more than only epithelial cells of the trachea. Analysis of tissues collected at early time points after experimental MV infection demonstrated the presence of MV-infected lymphoid and myeloid cells contacting respiratory tract epithelium in the absence of infected epithelial cells, suggesting that these immune cells seed the infection in vivo. Thereafter, lateral cell-to-cell spread of MV led to the formation of large foci of infected cells in the trachea and high levels of MV infection in the URT, particularly in the nasal cavity. These novel findings have important implications for our understanding of the high transmissibility of measles.
doi:10.1128/JVI.03258-12
PMCID: PMC3624209  PMID: 23365435
9.  Infection of the Upper Respiratory Tract with Seasonal Influenza A(H3N2) Virus Induces Protective Immunity in Ferrets against Infection with A(H1N1)pdm09 Virus after Intranasal, but Not Intratracheal, Inoculation 
Journal of Virology  2013;87(8):4293-4301.
The clinical symptoms caused by infection with influenza A virus vary widely and depend on the strain causing the infection, the dose and route of inoculation, and the presence of preexisting immunity. In most cases, seasonal influenza A viruses cause relatively mild upper respiratory tract disease, while sometimes patients develop an acute severe pneumonia. Heterosubtypic immunity induced by previous infections with influenza A viruses may dampen the development of clinical symptoms caused by infection with influenza A viruses of another subtype, as is the case during influenza pandemics. Here we show that ferrets acquire protective immunity after infection of the upper respiratory tract with a seasonal influenza A(H3N2) virus against subsequent infection with influenza A(H1N1)pdm09 virus inoculated by the intranasal route. However, protective heterosubtypic immunity was afforded locally, since the prior infection with the A(H3N2) virus did not provide protection against the development of pneumonia induced after intratracheal inoculation with the A(H1N1)pdm09 virus. Interestingly, some of these animals developed more severe disease than that observed in naïve control animals. These findings are of interest in light of the development of so-called universal influenza vaccines that aim at the induction of cross-reactive T cell responses.
doi:10.1128/JVI.02536-12
PMCID: PMC3624397  PMID: 23365444
10.  Characterization of the Mouse Neuroinvasiveness of Selected European Strains of West Nile Virus 
PLoS ONE  2013;8(9):e74575.
West Nile virus (WNV) has caused outbreaks and sporadic infections in Central, Eastern and Mediterranean Europe for over 45 years. Most strains responsible for the European and Mediterranean basin outbreaks are classified as lineage 1. In recent years, WNV strains belonging to lineage 1 and 2 have been causing outbreaks of neuroinvasive disease in humans in countries such as Italy, Hungary and Greece, while mass mortality among birds was not reported. This study characterizes three European strains of WNV isolated in Italy (FIN and Ita09) and Hungary (578/10) in terms of in vitro replication kinetics on neuroblastoma cells, LD50 values in C57BL/6 mice, median day mortality, cumulative mortality, concentration of virus in the brain and spinal cord, and the response to infection in the brain. Overall, the results indicate that strains circulating in Europe belonging to both lineage 1 and 2 are highly virulent and that Ita09 and 578/10 are more neurovirulent compared to the FIN strain.
doi:10.1371/journal.pone.0074575
PMCID: PMC3776840  PMID: 24058590
11.  T-Cell Infiltration Correlates with CXCL10 Expression in Ganglia of Cynomolgus Macaques with Reactivated Simian Varicella Virus 
Journal of Virology  2013;87(5):2979-2982.
Ganglia of monkeys with reactivated simian varicella virus (SVV) contained more CD8 than CD4 T cells around neurons. The abundance of CD8 T cells was greater less than 2 months after reactivation than that at later times and correlated with that of CXCL10 RNA but not with those of SVV protein or open reading frame 61 (ORF61) antisense RNA. CXCL10 RNA colocalized with T-cell clusters. After SVV reactivation, transient T-cell infiltration, possibly mediated by CXCL10, parallels varicella zoster virus (VZV) reactivation in humans.
doi:10.1128/JVI.03181-12
PMCID: PMC3571377  PMID: 23269790
12.  Novel Cyclovirus in Human Cerebrospinal Fluid, Malawi, 2010–2011 
Emerging Infectious Diseases  2013;19(9):1511-1513.
To identify unknown human viruses, we analyzed serum and cerebrospinal fluid samples from patients with unexplained paraplegia from Malawi by using viral metagenomics. A novel cyclovirus species was identified and subsequently found in 15% and 10% of serum and cerebrospinal fluid samples, respectively. These data expand our knowledge of cyclovirus diversity and tropism.
doi:10.3201/eid1909.130404
PMCID: PMC3810929  PMID: 23968557
Paraplegia; virus; cyclovirus; random amplification; cerebrospinal fluid; serum; viruses; Malawi
13.  Identification and Characterization of Two Novel Viruses in Ocular Infections in Reindeer 
PLoS ONE  2013;8(7):e69711.
A thorough understanding of virus diversity in wildlife provides epidemiological baseline information about pathogens. In this study, eye swab samples were obtained from semi-domesticated reindeer (Rangifertarandustarandus) in Norway during an outbreak of infectious eye disease, possibly a very early stage of infectious keratoconjunctivitis (IKC). Large scale molecular virus screening, based on host nucleic acid depletion, sequence-independent amplification and next-generation sequencing of partially purified viral nucleic acid, revealed the presence of a new papillomavirus in 2 out of 8 eye swab samples and a new betaherpesvirus in 3 out of 8 eye swab samples collected from animals with clinical signs and not in similar samples in 9 animals without clinical signs. Whether either virus was responsible for causing the clinical signs or in any respect was associated to the disease condition remains to be determined.
doi:10.1371/journal.pone.0069711
PMCID: PMC3713034  PMID: 23874987
14.  Complete Genome Sequence of Phocine Distemper Virus Isolated from a Harbor Seal (Phoca vitulina) during the 1988 North Sea Epidemic 
Genome Announcements  2013;1(3):e00291-13.
Phocine distemper virus (PDV) was identified as the cause of a large morbillivirus outbreak among harbor seals in the North Sea in 1988. PDV is a member of the family Paramyxoviridae, genus Morbillivirus. Until now, no full-genome sequence of PDV has been available.
doi:10.1128/genomeA.00291-13
PMCID: PMC3695424  PMID: 23814028
15.  The Future of Research and Publication on Altered H5N1 Viruses 
The Journal of Infectious Diseases  2012;205(11):1628-1631.
Recently, we and others obtained experimental evidence that highly pathogenic avian influenza virus subtype H5 can acquire the ability to transmit via aerosols between ferrets. Upon submission of manuscripts describing the results of these studies, the US National Science Advisory Board for Biosecurity was consulted and recommended that the main conclusions of the work be published but without the experimental details and mutation data that would enable replication of the experiments. Over the past few months, these events have led to intense discussions. Should this type of experiment be conducted? If so, under what conditions? Do the scientific and public health benefits of the work and its publication outweigh the potential risks? In February 2012, public health and influenza experts discussed these issues during a World Health Organization–organized technical consultation. This perspective article reviews the current state of the field and the recommendations made during the meeting.
doi:10.1093/infdis/jis257
PMCID: PMC3415850  PMID: 22454474
16.  Restricted Varicella-Zoster Virus Transcription in Human Trigeminal Ganglia Obtained Soon after Death 
Journal of Virology  2012;86(18):10203-10206.
We analyzed the varicella-zoster virus (VZV) transcriptome in 43 latently infected human trigeminal ganglia (TG) with postmortem intervals (PMIs) ranging from 3.7 to 24 h. Multiplex reverse transcriptase PCR (RT-PCR) revealed no VZV transcripts with a PMI of <9 h. Real-time PCR indicated a significant increase (P = 0.02) in VZV ORF63 transcript levels but not the virus DNA burden with longer PMI. Overall, both the breadth of the VZV transcriptome and the VZV ORF63 transcript levels in human cadaver TG increased with longer PMI.
doi:10.1128/JVI.01331-12
PMCID: PMC3446590  PMID: 22740396
17.  Recurring Influenza B Virus Infections in Seals  
Emerging Infectious Diseases  2013;19(3):511-512.
doi:10.3201/eid1903.120965
PMCID: PMC3647654  PMID: 23750359
influenza B virus; seals; serology; viruses; influenza; Suggested citation for this article: Bodewes R; Morick D; de Mutsert G; Osinga N; Bestebroer T; van der Vliet S; et al. Recurring influenza B virus infections in seals [letter]. Emerg Infect Dis [Internet]. 2013 Mar [date cited]. http://dx.doi.org/10.3201/eid1903.120965
18.  Evaluation of the 2009 WHO Dengue Case Classification in an Indonesian Pediatric Cohort 
The classification of dengue virus-infected patients continues to be a challenge to researchers and clinicians in the field. The accuracy of the 1997 World Health Organization (WHO) dengue case definition has been debated for a decade, because the definition was very stringent, for instance, several researchers showed that apparently severe cases were misclassified as not severe. Therefore the WHO issued revised guidelines in 2009. Here, we retrospectively compared the performance of the WHO case definition of 2009 with the WHO case definition of 1997 in a detailed documented pediatric cohort from Indonesia. Intensive treatment intervention was used as an indicator of severity of disease. In line with our expectations, the 2009 WHO case classification proved to be significantly more specific, albeit less sensitive than the WHO case classification of 1997. We conclude that the revised classification is promising both from research and clinical perspectives, but validation of the classification criteria still needs to be addressed.
doi:10.4269/ajtmh.2012.11-0491
PMCID: PMC3247126  PMID: 22232468
19.  Genomic Characterization of a Newly Discovered Coronavirus Associated with Acute Respiratory Distress Syndrome in Humans 
mBio  2012;3(6):e00473-12.
ABSTRACT
A novel human coronavirus (HCoV-EMC/2012) was isolated from a man with acute pneumonia and renal failure in June 2012. This report describes the complete genome sequence, genome organization, and expression strategy of HCoV-EMC/2012 and its relation with known coronaviruses. The genome contains 30,119 nucleotides and contains at least 10 predicted open reading frames, 9 of which are predicted to be expressed from a nested set of seven subgenomic mRNAs. Phylogenetic analysis of the replicase gene of coronaviruses with completely sequenced genomes showed that HCoV-EMC/2012 is most closely related to Tylonycteris bat coronavirus HKU4 (BtCoV-HKU4) and Pipistrellus bat coronavirus HKU5 (BtCoV-HKU5), which prototype two species in lineage C of the genus Betacoronavirus. In accordance with the guidelines of the International Committee on Taxonomy of Viruses, and in view of the 75% and 77% amino acid sequence identity in 7 conserved replicase domains with BtCoV-HKU4 and BtCoV-HKU5, respectively, we propose that HCoV-EMC/2012 prototypes a novel species in the genus Betacoronavirus. HCoV-EMC/2012 may be most closely related to a coronavirus detected in Pipistrellus pipistrellus in The Netherlands, but because only a short sequence from the most conserved part of the RNA-dependent RNA polymerase-encoding region of the genome was reported for this bat virus, its genetic distance from HCoV-EMC remains uncertain. HCoV-EMC/2012 is the sixth coronavirus known to infect humans and the first human virus within betacoronavirus lineage C.
IMPORTANCE
Coronaviruses are capable of infecting humans and many animal species. Most infections caused by human coronaviruses are relatively mild. However, the outbreak of severe acute respiratory syndrome (SARS) caused by SARS-CoV in 2002 to 2003 and the fatal infection of a human by HCoV-EMC/2012 in 2012 show that coronaviruses are able to cause severe, sometimes fatal disease in humans. We have determined the complete genome of HCoV-EMC/2012 using an unbiased virus discovery approach involving next-generation sequencing techniques, which enabled subsequent state-of-the-art bioinformatics, phylogenetics, and taxonomic analyses. By establishing its complete genome sequence, HCoV-EMC/2012 was characterized as a new genotype which is closely related to bat coronaviruses that are distant from SARS-CoV. We expect that this information will be vital to rapid advancement of both clinical and vital research on this emerging pathogen.
doi:10.1128/mBio.00473-12
PMCID: PMC3509437  PMID: 23170002
20.  The Multibasic Cleavage Site in H5N1 Virus Is Critical for Systemic Spread along the Olfactory and Hematogenous Routes in Ferrets 
Journal of Virology  2012;86(7):3975-3984.
The route by which highly pathogenic avian influenza (HPAI) H5N1 virus spreads systemically, including the central nervous system (CNS), is largely unknown in mammals. Especially, the olfactory route, which could be a route of entry into the CNS, has not been studied in detail. Although the multibasic cleavage site (MBCS) in the hemagglutinin (HA) of HPAI H5N1 viruses is a major determinant of systemic spread in poultry, the association between the MBCS and systemic spread in mammals is less clear. Here we determined the virus distribution of HPAI H5N1 virus in ferrets in time and space—including along the olfactory route—and the role of the MBCS in systemic replication. Intranasal inoculation with wild-type H5N1 virus revealed extensive replication in the olfactory mucosa, from which it spread to the olfactory bulb and the rest of the CNS, including the cerebrospinal fluid (CSF). Virus spread to the heart, liver, pancreas, and colon was also detected, indicating hematogenous spread. Ferrets inoculated intranasally with H5N1 virus lacking an MBCS demonstrated respiratory tract infection only. In conclusion, HPAI H5N1 virus can spread systemically via two different routes, olfactory and hematogenous, in ferrets. This systemic spread was dependent on the presence of the MBCS in HA.
doi:10.1128/JVI.06828-11
PMCID: PMC3302532  PMID: 22278228
21.  Picobirnaviruses in the Human Respiratory Tract 
Emerging Infectious Diseases  2012;18(9):1539-1540.
doi:10.3201/eid1809.120507
PMCID: PMC3437736  PMID: 22932227
human; picobirnavirus; respiratory tract; PCR; viruses
22.  Linking Influenza Virus Tissue Tropism to Population-Level Reproductive Fitness 
PLoS ONE  2012;7(8):e43115.
Influenza virus tissue tropism defines the host cells and tissues that support viral replication and contributes to determining which regions of the respiratory tract are infected in humans. The location of influenza virus infection along the respiratory tract is a key determinant of virus pathogenicity and transmissibility, which are at the basis of influenza burdens in the human population. As the pathogenicity and transmissibility of influenza virus ultimately determine its reproductive fitness at the population level, strong selective pressures will shape influenza virus tissue tropisms that maximize fitness. At present, the relationships between influenza virus tissue tropism within hosts and reproductive fitness at the population level are poorly understood. The selective pressures and constraints that shape tissue tropism and thereby influence the location of influenza virus infection along the respiratory tract are not well characterized. We use mathematical models that link within-host infection dynamics in a spatially-structured human respiratory tract to between-host transmission dynamics, with the aim of characterizing the possible selective pressures on influenza virus tissue tropism. The results indicate that spatial heterogeneities in virus clearance, virus pathogenicity or both, resulting from the unique structure of the respiratory tract, may drive optimal receptor binding affinity–that maximizes influenza virus reproductive fitness at the population level–towards sialic acids with α2,6 linkage to galactose. The expanding cell pool deeper down the respiratory tract, in association with lower clearance rates, may result in optimal infectivity rates–that likewise maximize influenza virus reproductive fitness at the population level–to exhibit a decreasing trend towards deeper regions of the respiratory tract. Lastly, pre-existing immunity may drive influenza virus tissue tropism towards upper regions of the respiratory tract. The proposed framework provides a new template for the cross-scale study of influenza virus evolutionary and epidemiological dynamics in humans.
doi:10.1371/journal.pone.0043115
PMCID: PMC3429484  PMID: 22952637
23.  Metagenomic Analysis of the Viral Flora of Pine Marten and European Badger Feces 
Journal of Virology  2012;86(4):2360-2365.
A thorough understanding of the diversity of viruses in wildlife provides epidemiological baseline information about potential pathogens. Metagenomic analysis of the enteric viral flora revealed a new anellovirus and bocavirus species in pine martens and a new circovirus-like virus and geminivirus-related DNA virus in European badgers. In addition, sequences with homology to viruses from the families Paramyxo- and Picornaviridae were detected.
doi:10.1128/JVI.06373-11
PMCID: PMC3302375  PMID: 22171250
24.  Novel Hepatitis E Virus in Ferrets, the Netherlands 
Emerging Infectious Diseases  2012;18(8):1369-1370.
doi:10.3201/eid1808.111659
PMCID: PMC3414025  PMID: 22840220
hepatitis E virus; viruses; ferrets; PCR; pyrosequencing; the Netherlands
25.  Marked Endotheliotropism of Highly Pathogenic Avian Influenza Virus H5N1 following Intestinal Inoculation in Cats 
Journal of Virology  2012;86(2):1158-1165.
Highly pathogenic avian influenza virus (HPAIV) H5N1 can infect mammals via the intestine; this is unusual since influenza viruses typically infect mammals via the respiratory tract. The dissemination of HPAIV H5N1 following intestinal entry and associated pathogenesis are largely unknown. To assess the route of spread of HPAIV H5N1 to other organs and to determine its associated pathogenesis, we inoculated infected chicken liver homogenate directly into the intestine of cats by use of enteric-coated capsules. Intestinal inoculation of HPAIV H5N1 resulted in fatal systemic disease. The spread of HPAIV H5N1 from the lumen of the intestine to other organs took place via the blood and lymphatic vascular systems but not via neuronal transmission. Remarkably, the systemic spread of the virus via the vascular system was associated with massive infection of endothelial and lymphendothelial cells, resulting in widespread hemorrhages. This is unique for influenza in mammals and resembles the pathogenesis of HPAIV infection in terrestrial poultry. It contrasts with the pathogenesis of systemic disease from the same virus following entry via the respiratory tract, where lesions are characterized mainly by necrosis and inflammation and are associated with the presence of influenza virus antigen in parenchymal, not endothelial cells. The marked endotheliotropism of the virus following intestinal inoculation indicates that the pathogenesis of systemic influenza virus infection in mammals may differ according to the portal of entry.
doi:10.1128/JVI.06375-11
PMCID: PMC3255817  PMID: 22090101

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