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1
Höfer, Chris Tina. "Influenza virus assembly." Doctoral thesis, Humboldt-Universität zu Berlin, Lebenswissenschaftliche Fakultät, 2015. http://dx.doi.org/10.18452/17251.
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Influenza A Viren besitzen ein segmentiertes, einzelsträngiges RNA-Genom, welches in Form viraler Ribonukleoprotein (vRNP)-Komplexe verpackt ist. Während das virale Genom im Zellkern repliziert wird, finden Assemblierung und Knospung reifer Viruspartikel an der apikalen Plasmamembran statt. Für die Virusbildung müssen die einzelnen viralen Komponenten hierher gebracht werden. Während intrinsische apikale Signale der viralen Transmembranproteine bekannt sind, sind der zielgerichtete Transport und der Einbau des viralen Genoms in neuentstehende Virionen noch wenig verstanden. In dieser Arbeit wurden potentielle Mechanismen des vRNP-Transportes untersucht, wie die Fähigkeit der vRNPs mit Lipidmembranen zu assoziieren und die intrinsische subzellulären Lokalisation des viralen Nukleoproteins (NP), eines Hauptbestandteils der vRNPs. Es konnte gezeigt werden, dass vRNPs nicht mit Lipidmembranen assoziieren, was mittels Flotation aufgereinigter vRNPs mit Liposomen unterschiedlicher Zusammensetzung untersucht wurde. Die Ergebnisse deuten jedoch darauf hin, dass das virale M1 in der Lage ist, Bindung von vRNPs an negativ-geladene Lipidmembranen zu vermitteln. Subzelluläre Lokalisation von NP wurde des Weiteren durch Expression fluoreszierender NP-Fusionsproteine und Fluoreszenzphotoaktivierung untersucht. Es konnte gezeigt werden, dass NP allein nicht mit zytoplasmatischen Strukturen assoziiert, stattdessen aber umfangreiche Interaktionen im Zellkern eingeht und mit hoher Affinität mit bestimmten Kerndomänen assoziiert, und zwar den Nukleoli sowie kleinen Kerndomänen, welche häufig in der Nähe von Cajal-Körperchen und PML-Körperchen zu finden waren. Schließlich wurde ein experimenteller Ansatz etabliert, welcher erlaubt, den Transport vRNP-ähnlicher Komplexe mittels Fluoreszenzdetektion aufzuzeichnen und Einzelpartikelverfolgungsanalysen durchzuführen. Unterschiedliche Phasen des vRNP-Transportes konnten beobachtet werden und ein 3-Phasen-Transportmodell wird skizziert.Influenza A viruses have a segmented single-stranded RNA genome, which is packed in form of viral ribonucleoprotein (vRNP) complexes. While the viral genome is replicated and transcribed in the host cell nucleus, assembly and budding of mature virus particles take place at the apical plasma membrane. Efficient virus formation requires delivery of all viral components to this site. While intrinsic apical targeting signals of the viral transmembrane proteins have been identified, it still remains poorly understood how the viral genome is transported and targeted into progeny virus particles. In this study, potential targeting mechanisms were investigated like the ability of vRNPs to associate with lipid membranes and the intrinsic ability of the viral nucleoprotein (NP) – which is the major protein component of vRNPs – for subcellular targeting. It could be shown that vRNPs are not able to associate with model membranes in vitro, which was demonstrated by flotation of purified vRNPs with liposomes of different lipid compositions. Results indicated, however, that the matrix protein M1 can mediate binding of vRNPs to negatively charged lipid bilayers. Intrinsic subcellular targeting of NP was further investigated by expression of fluorescent NP fusion protein and fluorescence photoactivation, revealing that NP by itself does not target cytoplasmic structures. It was found to interact extensively with the nuclear compartment instead and to target specific nuclear domains with high affinity, in particular nucleoli and small interchromatin domains that frequently localized in close proximity to Cajal bodies and PML bodies. An experimental approach was finally established that allowed monitoring the transport of vRNP-like complexes in living infected cells by fluorescence detection. It was possible to perform single particle tracking and to describe different stages of vRNP transport between the nucleus and the plasma membrane. A model of three-stage transport is suggested.
2
Mittelholzer, Camilla Maria. "Influenza virus - protection and adaptation /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-656-5/.
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Green, P. C. "Serological and immunocytochemical studies on influenza virus and influenza virus infected cells." Thesis, University of Manchester, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.356114.
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Wallensten, Anders. "Influenza A virus in wild birds." Doctoral thesis, Linköping : Linköping University, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-7643.
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Morgan, David John. "Defective interfering influenza virus reverses the immunopathological effects of standard influenza virus in mice." Thesis, University of Bristol, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.332491.
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6
Seekings, Amanda Hanna. "Emergence of H7 highly pathogenic avian influenza virus from low pathogenicity avian influenza virus." Thesis, Imperial College London, 2017. http://hdl.handle.net/10044/1/52910.
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Outbreaks of highly pathogenic avian influenza virus (HPAIV) may result in the infection of millions of poultry, causing devastating disease and up to 100% mortality. Avian influenza outbreaks and laboratory experiments have shown that HPAIV can emerge from low pathogenicity avian influenza virus (LPAIV) precursors. The multi-basic cleavage site (MBCS) in the haemagglutinin protein is described as the main pathogenic determinant of HPAIV infection in poultry. Identifying a precursor LPAIV is important for understanding the molecular changes involved in the emergence of HPAIV. In 2008, H7N7 HPAIV was confirmed in Oxfordshire, UK. The presence of a LPAIV precursor with a rare di-basic cleavage site (DBCS) was identified. The DBCS contains an additional basic amino acid compared to common circulating LPAIVs that harbour a single basic amino acid at the cleavage site (SBCS). Using reverse genetics, isogenic viruses based on A/chicken/England/11406/2008 H7N7 HPAIV, from the outbreak, were rescued with the MBCS replaced with either a DBCS (H7N7DB) as seen in the putative LPAIV precursor or a SBCS representative of common H7 LPAIVs (H7N7SB). Intravenous pathogenicity index testing of the recombinant viruses confirmed that only the MBCS conferred the highly pathogenic phenotype. Following passage in ovo, H7N7DB showed evidence of spontaneous evolution to a HPAIV genotype and phenotype as demonstrated by the acquisition of a MBCS, and by influenza virus-specific immunohistochemistry staining in embryo vascular endothelial cells. In contrast, deep sequencing of tissues from embryos in which H7N7SB was serially passaged up to three times showed retention of the LPAIV genotype. Thus, in chicken embryos, an H7N7 virus containing a DBCS displays an unstable nature allowing for rapid evolution to HPAIV. In ovo passage presents a novel approach to assess the likelihood of a LPAIV to evolve into HPAIV, and allows a laboratory-based dissection of molecular mechanisms behind the emergence of HPAIV.
7
Jia, Nan. "Glycobiology studies of influenza virus." Thesis, Imperial College London, 2015. http://hdl.handle.net/10044/1/50787.
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Glycans represent a class of macromolecules that exhibit vital biological roles in living organisms. They are not only essential for maintaining the normal functionalities of a cell, but are also involved in many pathogenic processes. The influenza A virus binds to glycan receptors that are expressed on the surface of respiratory epithelial cells of human airway and thereby initiates infection. Deciphering the structural features of glycans and comprehending their functional implications are thus crucial to expand our understandings of the disease. To validate the alternative models that are used in the studies of influenza, we generated the glycomic profiles from in vivo and in vitro experimental systems by mass spectrometry. A combination of MALDI-TOF MS, MALDI-TOF-TOF MS/MS, GC-EI-MS and enzymatic digestion experiments were utilised to characterise the structure of glycans. The ferret has been used as an experimental animal to investigate the transmission and replication of influenza viruses. To verify the validity of this model, we carried out glycomic characterisation of ferret respiratory tissues to complement the data that was generated from human airway tissues. The mass spectrometric analysis indicates that the respiratory glycosylation of ferret highly resembles that of human, although distinctive expression of glycans displaying the Sda epitope are detected exclusively in ferret. Nonetheless, in comparison to other lab animals such as mouse and swine, ferret remains a better alternative model for studying the pathogenicity of influenza viruses. In the second project, we generated the glycomic profiles from human and ferret respiratory epithelial cells that were cultured under experimental conditions. Glycosylation patterns between these two in vitro systems are largely comparable, except the presence of the Sda epitope in ferret cells. However, when compared to their corresponding in vivo tissues, diminished structural repertoires especially the high-mass structures were observed.
8
Read, Eliot Keith Curtis. "Investigating influenza A virus RNA trafficking." Thesis, University of Cambridge, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.609127.
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Tan, E.-Pien. "Screening for influenza virus resistance genes." Thesis, University of Cambridge, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.608229.
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Kudryavtseva, Katerine. "Genome packaging in influenza A virus." Thesis, University of Cambridge, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.648592.
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Lau, Lee-hang Lincoln, and 劉力恆. "Influenza virus shedding and transmission in households." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hdl.handle.net/10722/196093.
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Background The dynamics of influenza virus transmission are not yet fully understood, hindering the appropriate development and implementation of control and mitigation strategies. One major uncertainty relates to the profile of infectiousness over time in humans infected by influenza virus, and how variation in infectiousness might contribute to the risk of transmission in households.
Methods In 2008 and 2009, two large community-based studies were conducted to study the household transmission of influenza viruses in Hong Kong. I analyzed data on viral shedding and disease in participants, and used statistical models to examine how viral shedding patterns and other factors might affect the risk of influenza virus transmission in households, both within individuals over time, and between individuals with different patterns in viral shedding.
Results The patterns of viral shedding relative to the time of illness (acute respiratory illness; ARI) onset in naturally acquired infections were found to be largely comparable to the patterns observed in experimental infections. Viral shedding detected by RT-PCR peaks around the day of ARI onset after which levels of shedding declined over around 7 days, and viral shedding tended to be greater in children than adults. The patterns of viral shedding in cases of seasonal A subtypes were similar, although the trends of shedding in cases of seasonal B differed with some indication of a plateau in shedding for up to 5 days after illness onset. The risk of household influenza transmission was significantly associated with log10 viral shedding, though not with influenza related signs and symptoms such as cough.
Conclusions The patterns of viral shedding observed in naturally-acquired influenza A virus infections correlated with the pattern of infectiousness over time after onset of illness. The majority of infectiousness was estimated to occur within 2-3 days of illness onset, with implications for isolation strategies. The heterogeneous nature of individual viral shedding suggests the possibility of substantial variation in infectiousness, particularly among children.published_or_final_version
Community Medicine
Doctoral
Doctor of Philosophy
12
Lau, Siu-ying, and 劉韶瑩. "Characterizations of antigenic and receptor binding properties of avian H5N1 and 2009 pandemic H1N1 viruses." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B47165078.
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Avian H5N1 viruses have perpetuated in poultry and caused sporadic human transmission since 1997. Vaccine candidates for the potential pandemic caused by H5N1 viruses have been continuously updated by World Health Organization. Multiple genetic lineages of H5N1 viruses which co-circulate and rapidly evolve in different regions, together with periodic population replacement of newly emerged genetic and antigenic variants in the field, pose great challenge for H5N1 vaccine candidate selection. The complexity of avian H5N1 viruses evolution raises an important issue for studying antigenic properties and also for projecting antigenic trend of this virus since the model established for the seasonal influenza viruses may not apply to H5N1 viruses which they are still in the animal phase. In contrast, the 2009 pandemic H1N1 viruses have established as another seasonal influenza viruses in humans. How will this swine originated viruses evolve genetically and antigenically in humans? For the first in human history, we are able to track the changes of pandemic viruses from the very beginning when they transmitted to human.
This study focuses on antigenic and receptor binding properties of avian
H5N1 viruses from 1997 to 2010 and 2009 pandemic H1N1 viruses from 2009 to 2011. It is found that avian H5N1 viruses continue to display highly diverse antigenic profile. The newly emerged H5N1 virus variants of clade 2.3.4 in 2008 and clade 2.3.2 in 2010 exhibit distinct antigenic properties as compared to the genetically similar viruses that were characterized previously. Receptor binding analysis showed H5N1 viruses still exhibit binding preference for avian type receptor. However, analysis of escape mutants selected from H5N1 viruses exposed to H5 monoclonal antibodies in cell based assay indicates that mutations in the conserved sites may cause switch of receptor binding specificity to human type or dual specificity for both human and avian.
Based on antigenic and receptor binding analyses, it is found that the 2009 pandemic H1N1 viruses isolated from 2009 to 2011 are relatively stable. Most of the antigenic variants to monoclonal antibodies are transient and not able to become prevalent. It remains to be investigated if more significant antigenic variants may emerge in the coming seasons when population immunity prevails this virus.
In conclusion, this study showed that clade 2.3 avian H5N1 viruses become increasingly antigenic distinct as compared to clade 2.1 and 2.2 viruses. Antigenic variation in antigenic sites may change receptor binding specificity in avian H5N1 viruses. The 2009 pandemic H1N1 viruses remain stable up to date but continue monitoring in coming seasons is necessary.published_or_final_version
Microbiology
Master
Master of Philosophy
13
Cheng, Ka-yeung, and 鄭家揚. "Diagnosis and surveillance of human influenza virus infection." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hub.hku.hk/bib/B48079819.
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Background: Early and accurate diagnosis of influenza helps start correct treatment and
prevention strategies at individual level. Ongoing systematic collection, analysis and
dissemination of the surveillance data from aggregated diagnostic results and other early
indicators help gather the foremost disease information for all subsequent control and
mitigation strategies in the community. Disease information from surveillance results then
feed back to medical practitioners for improving diagnosis. By improving this loop of
disease information transfer in terms of accuracy and timeliness, interventions for disease
control can be applied efficiently and effectively.
Methods: Several new influenza diagnosis and surveillance methods were explored and
evaluated by comparing with laboratory reference test results. Logistic regression models
were applied to synthesize a refined clinical guideline for human influenza infections. The performance of QuickVue rapid diagnostic test was evaluated in a community setting.
Weekly positive rates from the above two diagnostic methods, together with three other
different syndromic surveillance systems, including data from school absenteeism, active
telephone survey and internet based survey were evaluated according to the US CDC
public health surveillance systems guideline in terms of their utility, correlations and
aberration detection performance. Different combinations of surveillance data streams and
aberration detection algorithms were evaluated to delineate the optimal use of multi-stream
influenza surveillance data. A framework of efficient surveillance data dissemination was
synthesized by incorporating the merits of the online national surveillance websites and the
principles of efficient data presentation and dashboard design.
Results: A refined clinical diagnostic rule for influenza infection using fever, cough runny
nose and clinic visit during high influenza activity months as predictors was scored the
highest amount all other current clinical definitions. Time series weekly positive rate from
this rule showed better correlation with reference community influenza activity than many
other current clinical influenza definitions. The QuickVue rapid diagnostic test has an
overall diagnostic sensitivity of 68% and specificity 96%, with an analytic sensitivity
threshold of 105 to106 viral copies per ml. Weekly aggregated QuickVue and school
absenteeism surveillance data was found to be highly correlated with hospital laboratory
and community sentinel surveillance data, but the telephone and internet survey was only
moderately correlated. Multiple univariate methods performed slightly better than
multivariate methods for aberration detections in general. More sophisticated outbreak
detection algorithms did not result in significant improvement of outbreak detectionpublished_or_final_version
Community Medicine
Doctoral
Doctor of Philosophy
14
Poon, Leo L. M. "The polyadenylation of influenza virus mRNA." Thesis, University of Oxford, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.312548.
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Bishop, K. J. "Study of influenza A virus ribonucleoproteins." Thesis, University of Cambridge, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.596669.
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Two expression systems were utilised in an attempt to produce suitable quantities of the influenza polymerase proteins for protein purification. Using the methylotrophic yeast Pichia pastoris, both PB1 and PB2 were expressed at around 0.1-0.4 mg/l. However, it did not prove possible to purify the polypeptides which appeared to be aggregated. The P proteins and NP were also expressed in mammalian cells using recombinant Semliki Forest viruses. However, soluble protein did not accumulate at levels sufficient for large scale purification studies. A transient "reverse genetics" assay whereby the expression of a synthetic model viral RNA segment is driven by influenza P proteins expressed by recombinant vaccinia viruses and NP from a T7 driven plasmid, was used for the analysis of mutant influenza proteins in the processes of viral transcription and replication. Recombinant vaccinia viruses expressing mutant forms of PB1 were generated and their ability to support viral replication determined. One mutant which was shown not to bind PB2 retained reduced but signifciant replication activity. In contrast, mutants that were unable to bind PA were defective in viral RNA synthesis. Of the mutants that were defective in viral transcription, one acted as a trans-dominant inhibitor of wild type protein function. Mutants that were unable to bind RNA were unable to support viral transcription, whilst those with reduced RNA binding capacity were similarly impaired in transcription. The mutants that were unable to bind RNA were also shown to be transdominant inhibitors of replication, indicating that they were able to compete with wild type NP for essential components of the transcription machinery. Mutations in the N-terminal region of NP previously described as the karyopherin α binding site were also analysed for their ability to support viral transcription. Neither mutation of a residue described as essential for karyopherin α binding nor deletion of the karyopherin α binding site affected viral RNA synthesis, though these mutants localised in the cell differently to wild type NP.
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Duhaut, Susan. "The assembly of influenza virus ribonucleoproteins." Thesis, University of Reading, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.306344.
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Lam, Tsan-yuk Tommy. "Molecular evolution and epidemiology of influenza A virus." Click to view the E-thesis via HKUTO View the Table of Contents & Abstract, 2010. http://sunzi.lib.hku.hk/hkuto/record/B44137084.
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Wen, Xi, and 溫茜. "Study of nuclear factor 90 against influenza A virus." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2013. http://hdl.handle.net/10722/208613.
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Influenza A virus is one of the most common human pathogens which caused considerable disease burdens through annual epidemics and occasional pandemics. The consequences vary from mild to severe or even fatal. What are the host and viral elements which determine the consequence of infection? In the past 15 years, several avian influenza A viruses including H5N1, H9N2, H7N7 and H7N9 subtypes were found to cross host barrier and infect humans. Question about how avian influenza A viruses gained the ability to replicate in human cells remains unanswered. Studies on host factors associated with virus replication would provide important information for understanding host restriction, virus pathogenesis and for antiviral drug development. Nuclear factor 90 (NF90) is a host protein identified in our previous study to inhibit influenza A virus replication. Antiviral activity of NF90 was also found for other viruses. However, detailed mechanisms for the antiviral function of NF90 remains largely unknown. This study is focused on NF90’s antiviral functions through exploring its relationship with PKR activation and stress granules formation using influenza A virus as a model.
I characterized the interaction between NF90 and PKR, and showed the C-terminal of NF90 interacts with PKR in an RNA-binding dependent manner. Using transient and stable NF90 knockdown cells, I found that NF90 is required for PKR activation upon stimulation by dsRNA or infection with a NS1 mutated virus. PKR activation leads to the formation of stress granules and stall of protein translation. I found that NF90 is a core component of stress granules, which may underlie the mechanism for the antiviral activity of NF90. However, NF90 may also complete with PKR for RNA binding and regulate PKR activation.
To further delineate the interaction between NF90 and PKR by using influenza A virus, my study constructed a panel of NS1 mutant viruses which were attenuated in antagonizing specific host antiviral pathways. I characterized the NS1 123-127 mutant virus which is unable to inhibit PKR phosphorylation but retained other functions unaffected. It was demonstrated that NF90 mediates PKR-dependent antiviral pathway since NS1 123-127 mutant virus replicated to a comparable level as wild type virus in the NF90 knockdown but not scramble knockdown 293T cells or in the interferon deficient Vero cells. This study for the first time found NF90 serves as a regulator of PKR antiviral pathway.
To understand the mechanism for NF90 inhibition of influenza A virus replication, I found that NP, but not the other polymerase subunits, of influenza A virus was targeted to the stress granules. Since NF90 interacts with NP, it is reasonable to postulate that NF90 mediates the localization of NP, and possibly viral mRNA, to the stress granules in order to inhibit influenza A virus replication through regulation of proteins synthesis.
In summary, my study provided comprehensive evidence to support a novel NF90-PKR antiviral pathway and suggests that NF90 may play critical roles to balance PKR phosphorylation in response to virus infection in cells.published_or_final_version
Microbiology
Doctoral
Doctor of Philosophy
19
Guan, Jing, and 管静. "The role of virus-specific human T cells in influenza A virus infection." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hdl.handle.net/10722/208423.
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Influenza A virus infection is a major cause of human morbidity and mortality. T cell
immunity is believed to play critical roles for host defenses against influenza A infection.
Once intracellular influenza A infection is established, viral clearance is mainly dependent on
virus-specific CD8+ T cells. CD4+ T cells are important for adaptive immunity to natural
influenza A infection or vaccination by providing help to B cells for antibody production and
also providing help to CD8+ T cells for the generation of cytotoxicity. In addition, virusspecific
CD4+ and CD8+ T cells are rich sources of effector cytokines, such as IFN-and
TNF-, which can promote the function of antigen presenting cells and have direct antiviral
activity. Cross-subtype reactive CD4+ and CD8+ memory T cells also affect the clearance of
virus infection even in those who lack virus-specific antibodies. Therefore, the aim of our
study is to assess the influenza virus-specific T cell responses and define their possible
protective role in pandemic H1N1 virus and seasonal influenza infection in human.
First we determined whether healthy adults have the cross-reactivity of memory CD4+ and
CD8+ T cells against pandemic virus. In April of 2009, 7 pandemic H1N1 infected patients
and 17 their healthy contacts who had no pandemic influenza infection were recruited in this
study. By using intracellular IFN-staining and flow cytometry, we examined their pandemic
H1N1 virus and seasonal influenza H1N1-specific CD4+ and CD8+ T cell responses. Healthy
contacts did have measurable but low frequencies of cross-reactive influenza-specific CD4+
and CD8+ T cells, though the frequencies of these T cells specific to pandemic H1N1 virus
were slightly lower than that specific to seasonal H1N1 virus. Furthermore, when compared
the pandemic H1N1-specific T cell responses between healthy contacts and patients with
pandemic H1N1 infection, we can found that the healthy contacts have higher pandemic
H1N1 specific-T cell responses than patients, suggesting these pre-existing pandemic H1N1
specific-T cells may have protection from pandemic influenza virus infection.
In addition, we conducted a prospective T cell immunity and influenza surveillance study in a
cohort of more than 200 healthy volunteers before the influenza season and investigated
whether the pre-existing T cell immunity is related to the protection from influenza infection
in the next coming influenza season. Using intracellular IFN-staining assay, we examined
their pre-existing seasonal influenza H1N1, H3N2, seasonal influenza B virus-specific CD4+
and CD8+ T cell responses. Due to the small number of cases of influenza infection in the
coming influenza season, the results only showed a trend that the subjects who have higher
frequency of influenza virus strain-specific T cells may have lower chance to suffer from
same strain of influenza infection, which to some extent, reflect the pre-exist memory T cells
have association with the protection in the coming influenza season.
In conclusion, T cells play an important role in defensing against influenza infection. The
higher influenza virus specific-T cells response activity in healthy adults may have a
protection against influenza virus infection.published_or_final_version
Paediatrics and Adolescent Medicine
Master
Master of Philosophy
20
Ling, Man-to. "The role of mannose binding lectin in influenza virus infection." Click to view the E-thesis via HKUTO, 2009. http://sunzi.lib.hku.hk/hkuto/record/B43085295.
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Lam, Tsan-yuk Tommy, and 林讚育. "Molecular evolution and epidemiology of influenza A virus." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2010. http://hub.hku.hk/bib/B44137084.
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Sun, Jian. "Computer-aided drug design for influenza A virus." Click to view the E-thesis via HKUTO, 2009. http://sunzi.lib.hku.hk/hkuto/record/B44205156.
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Lu, Lu. "Transmission dynamics of Avian Influenza A virus." Thesis, University of Edinburgh, 2015. http://hdl.handle.net/1842/10481.
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Influenza A virus (AIV) has an extremely high rate of mutation. Frequent exchanges of gene segments between different AIV (reassortment) have been responsible for major pandemics in recent human history. The presence of a wild bird reservoir maintains the threat of incursion of AIV into domestic birds, humans and other animals. In this thesis, I addressed unanswered questions of how diverse AIV subtypes (classified according to antigenicity of the two surface proteins, haemagglutinin and neuraminidase) evolve and interact among different bird populations in different parts of the world, using Bayesian phylogenetic methods with large datasets of full genome sequences. Firstly, I explored the reassortment patterns of AIV internal segments among different subtypes by quantifying evolutionary parameters including reassortment rate, evolutionary rate and selective constraint in time-resolved Bayesian tree phylogenies. A major conclusion was that reassortment rate is negatively associated with selective constraint and that infection of wild rather than domestic birds was associated with a higher reassortment rate. Secondly, I described the spatial transmission pattern of AIV in China. Clustering of related viruses in particular geographic areas and economic zones was identified from the viral phylogeographic diffusion networks. The results indicated that Central China and the Pearl River Delta are two main sources of viral out flow; while the East Coast, especially the Yangtze River delta, is the major recipient area. Simultaneously, by applying a general linear model, the predictors that have the strongest impact on viral spatial diffusion were identified, including economic (agricultural) activity, climate, and ecology. Thirdly, I determined the genetic and phylogeographic origin of a recent H7N3 highly pathogenic avian influenza outbreak in Mexico. Location, subtype, avian host species and pathogenicity were modelled as discrete traits and jointly analysed using all eight viral gene segments. The results indicated that the outbreak AIV is a novel reassortant carried by wild waterfowl from different migration flyways in North America during the time period studied. Importantly, I concluded that Mexico, and Central America in general, might be a potential hotspot for AIV reassortment events, a possibility which to date has not attracted widespread attention. Overall, the work carried out in this thesis described the evolutionary dynamics of AIV from which important conclusions regarding its epidemiological impact in both Eurasia and North America can be drawn.
24
Ma, Siu-kit. "Genesis and prevalence of H1N2 swine influenza virus in pigs from southern China /." View the Table of Contents & Abstract, 2005. http://sunzi.lib.hku.hk/hkuto/record/B31495072.
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Ma, Siu-kit, and 馬少傑. "Genesis and prevalence of H1N2 swine influenza virus in pigs from southern China." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2005. http://hub.hku.hk/bib/B4501033X.
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Leung, Yin-hung Connie, and 梁彥虹. "Ecology, epidemiology and immunology of avian influenza virus." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B46329626.
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Jagger, Brett William. "The influenza A polymerase in viral pathogenesis." Thesis, University of Cambridge, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.610897.
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Lee, Hung-chiu. "Synthetic RNA interference against influenza A virus." Click to view the E-thesis via HKUTO, 2005. http://sunzi.lib.hku.hk/hkuto/record/B35537814.
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Lee, Hung-chiu, and 李洪釗. "Synthetic RNA interference against influenza A virus." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2005. http://hub.hku.hk/bib/B35537814.
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Wasson, Peter Stewart. "Development of novel virus vectors for influenza vaccination." Thesis, University of Edinburgh, 2012. http://hdl.handle.net/1842/6492.
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The influenza virus, a member of the Orthomyxoviridae family, causes regular, large-scale morbidity and mortality in birds and humans and significant human suffering and economic loss. The primary aim of this study was to develop a novel influenza vaccine. Vaccines are an essential tool for the control of influenza because they increase resistance to infection, prevent illness and death and help to limit virus transmission to other birds and mammals, including humans. By reducing the environmental contamination of influenza virus in global poultry stocks, the risk of a new pandemic virus being generated by the human-avian link is diminished. Marek’s Disease is a common lymphoproliferative disease of poultry that is readily controlled worldwide using the live attenuated vaccine, CVI988. The Marek’s Disease Virus (MDV) CVI988 viral genome, available as a Bacterial Artificial Chromosome (BAC), forms viable infectious viral particles when transfected into Chicken Embryo Fibroblast (CEF) cells. Using BAC mutagenesis, two non-essential genes in the MDV CVI988 BAC (UL41 and US10), were identified and replaced by the low pathogenic influenza haemagglutinin 10 (H10) gene. These live recombinant MDV-H10 vectors will allow simultaneous vaccination against both pathogens. In addition, the non-essential genes were also replaced with GFP creating MDV-GFP constructs. Both genes were expressed initially using a CMV promoter, although this disrupted the MDV CVI988 BAC; a second promoter, PGK-1, proved more successful. A third MDV gene (UL50) was deleted, but severe attenuation prevented the incorporation of H10 into this open reading frame. Future work to test the MDV-HA constructs in vivo will be carried out in collaboration with the Istituto Zooprofilattico Sperimentale delle Venezie in Italy. In addition, development of MDV constructs containing multiple HA genes (H10 and H5) linked by the 2A polyprotein can be developed with the goal of establishing heterosubtypic immunity.
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Föglein, Ágnes. "Cell biology of the influenza A virus polymerase." Thesis, University of Cambridge, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.609935.
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Pascolutti, Mauro. "The Development of Carbohydrate-Based Probes of Influenza Virus Sialidase." Thesis, Griffith University, 2013. http://hdl.handle.net/10072/366410.
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Influenza is a significant human disease, as evidenced by seasonal epidemics that exact a high toll in morbidity and mortality, and worldwide pandemics, for example the 2009 'swine-origin' influenza A pandemic. Two influenza virus-specific drugs, Relenza® and Tamiflu®, target the viral enzyme sialidase, and are effective against all wild type influenza virus strains. Resistance development to the more widely used drug, Tamiflu®, however, and new insights into the sialidase structure, have fuelled a drive to develop new sialidase inhibitors. The research described in this PhD thesis is focused on the development of novel carbohydrate-based inhibitors of influenza virus sialidase. This enzyme plays an important role in the process of infection by facilitating the release of new virus particles from the infected host cell. Inhibition of the viral sialidase leaves new virus particles clumped at the infected cell surface, thus reducing propagation of infection. Recent X-ray crystal structures of a sub-group of influenza A virus sialidases, which includes the important N1 sialidases, have revealed a previously unanticipated cavity adjacent to the enzyme active site, which is formed upon the opening of a flexible protein loop (the 150-loop). This offers the potential for the design of new sialidase inhibitors that target the open 150-loop conformation of the protein. Work published in the von Itzstein group has shown that suitable C-linked functionality introduced at the C3 position of the general sialidase inhibitor Neu5Ac2en, can extend into the 150-cavity and lock the flexible 150-loop in an open conformation. The research undertaken in this work, to further explore inhibition of influenza virus sialidase by targetting the 150-cavity, involved the synthesis of 3-O- and 3-N-substituted Neu5Ac2en derivatives.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
Institute for Glycomics
Science, Environment, Engineering and Technology
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Pavan, Carmen M. "Influenza B virus : segment 7 gene expression." Thesis, McGill University, 1989. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=55673.
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Smith, D. B. "The production of influenza virus spliced mRNAs." Thesis, University of Cambridge, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.355039.
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Jung, Tanis E. "Mutational analysis of the influenza virus polymerase." Thesis, University of Oxford, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.426398.
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Harvey, Ruth. "Studies of influenza A virus H5 haemagglutinin." Thesis, University of Reading, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.270832.
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Tibbles, K. W. "Studies on the influenza virus RNA polymerase." Thesis, University College London (University of London), 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.380686.
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Blok, Vivian Carol. "Studies of the influenza virus RNA polymerase." Thesis, University of Cambridge, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.292959.
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Doty, Daniel S. M. Massachusetts Institute of Technology. "CD8⁺ T Cell Response to Influenza Virus." Thesis, Massachusetts Institute of Technology, 2005. http://hdl.handle.net/1721.1/86280.
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Thesis: S.M., Massachusetts Institute of Technology, Department of Biology, 2005.Cataloged from PDF version of thesis.
Includes bibliographical references (pages 10-12).
The flu is an extremely prevalent and potentially devastating disease, especially dangerous to the very young, the elderly, and to people with compromised immune systems. Influenza has a characteristic course of infection, and is often effectively dispatched by the immune system. The cell-mediated lysis of infected cells is a particularly important step in clearing the infection. Antigen specific CD8+ T lymphocytes are selected and activated in the mediastinal lymph node, proliferate and gain effector function, then migrate to the lungs, where they selectively destroy infected cells. The CD8+ effector population pool undergoes a phase of contraction, when most effector cells die. Those that survive become memory T cells, protecting the body from subsequent influenza infections. The molecular and cellular interactions that comprise the CD8+ cytotoxic T cell response to influenza virus are of particular interest because of their implications for the prevention, treatment, and alleviation of the flu.
by Daniel Doty.
S.M.
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Pappworth, Isabel Yseult. "Studies in influenza A virus induced apoptosis." Thesis, University of Birmingham, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.434078.
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Influenza viruses induce apoptosis in tissue culture cells in vitro. In a study to examine the role of individual genes in apoptosis a twelve plasmid based reverse genetic system was used to produce a series of viruses, these being: rA/Victoria and rA/WSN, recombinant forms of the parent viruses A/Victoria/75 (H3N2) and A/WSN/33 (H1N1), rA/Vic/WSNNP and rA/Vic/WSNM, recombinant A/Victoria based viruses with the A/WSN nucleoprotein (NP) and matrix (M) gene respectively. These viruses were examined for their ability to induce apoptosis (determined morphologically), cell lysis (determined by lactate dehydrogenase release) and infection (determined by antibody labelling of nucleoprotein [NP]). Virus replication assays were also performed. The rA/WSN virus behaved differently to rA/Victoria and rA/Vic/WSNNP. A difference in the proportions of morphological apoptosis and cell lysis induced at 24 hours p.i. was observed. When these two measurements were taken over time it was seen that the rA/Victoria and rA/Vic/WSNNP infected cells progressed through apoptosis at a faster rate with more cells lysed at 24 hours post infection than cells infected with the rA/WSN virus. Other viruses that were thought to be reassortants of A/Victoria/75 and A/WSN/33 were found not to be, and were instead clone 7a (a reassortant of A/England/939/69 and A/Puerto Rico/8/34 parents) used in the laboratory. Clone 7a infected cells behaved similarly to rA/WSN infected cells in that progression through apoptosis was slower than for rANictoria and rANic/WSNNP infected cells. Clone 7a replicated to a higher titre and over a more prolonged period suggesting that the purpose of the delay may be to enhance replication. However, inhibition of apoptosis by the pan-caspase inhibitor (z-VAD-fmk) did not affect replication of clone 7a, rA/Victoria or rA/Vic/WSNNP.
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Sieben, Christian. "Host cell invasion by influenza A virus." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2013. http://dx.doi.org/10.18452/16743.
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Influenzaviren müssen in die Wirtszelle aufgenommen werden, um dort ihr Genom freizusetzen und ihre Replikation mit Hilfe des Reproduktionsapparats der Zelle einzuleiten. Der komplexe Replikationszyklus der Influenza A Viren ist noch nicht vollständig verstanden. Er beginnt mit der Bindung des viralen Hämagglutinins (HA) an Sialinsäure (SA) auf der Zelloberfläche der Wirtszelle. In dieser Arbeit wurde die Virusbindung an Zellen mit unterschiedlicher Rezeptorkomposition verglichen. Dabei konnte gezeigt werden, dass für die zelluläre Spezifität die Präsentation des Rezeptors innerhalb der Plasmamembran der Zelle eine größere Rolle spielt als die Struktur des Rezeptorglykans selbst. Des Weiteren deuten die Beobachtung sehr kleiner Kräfte und ein stufenweises Öffnen von Bindungen auf eine multivalente Interaktion hin. Multivalenz wird oft in biologischen Bindungsprozessen beobachtet und kann Bindungskräfte enorm verstärken. Basierend auf diesen Ergebnissen wurden inhibitorische Nanopartikel entwickelt, die die natürliche Zelloberfläche als hochaffine Bindungsalternative imitieren. Verschiedenartige Nanopartikel wurden evaluiert und konnten die Virusaktivität um mehr als 80 % hemmen. Nach der Bindung wird das Virus durch Endozytose in die Zelle aufgenommen. Durch spezifische Virusmarkierung und gleichzeitiger Expression von zellulären Markerproteinen wurde der Transport einzelner Viren in lebenden Zellen verfolgt. Dabei konnte gezeigt werden, dass das Virus sowohl durch frühe, als auch durch späte Endosomen wandern muss, um sein Genom erfolgreich in das Zytoplasma zu entlassen. Außerdem verzögert das Virus die endosomale Ansäuerung um eine optimale Aufenthaltsdauer im Endosom und die lokalisierte Fusion in der Nähe des Zellkerns zu gewährleisten. Pharmakologisches Eingreifen in diese Prozesse konnte zudem weitere kritische Faktoren identifizieren, die die Effizienz der Virusinfektion stark beeinflussen.Influenza virus must enter a host cell to deliver its genome, use the cells reproductive machinery and eventually initiate its replication. The replication cycle of influenza A virus is very complex and still not fully understood. It generally starts with binding of the viral protein hemagglutinin (HA) to its cellular receptor sialic acid (SA). In this work, virus-cell attachment forces were investigated at the single molecule level using intact virus binding to living cells, a set-up that closely mimics the in vivo situation. Cells of different surface SA composition were compared. It could be shown that the unique presentation of the ligand within the cells plasma membrane, rather than the structure of the receptor-glycan itself, strongly affects cellular specificity. The low binding forces as well as the observation of stepwise unbinding events suggest a multivalent interaction type. Based on this finding, inhibitory nanoparticles mimicking the cell surface were constructed. Different particles were evaluated and shown to efficiently inhibit virus infection by ≥ 80 %. Since many molecular details of multivalent interactions remain poorly understood parameters such as ligand spacing and presentation were varied and revealed that the density of ligands as well as the interacting surface plays critical roles for virus inhibition. Upon attachment, the virus enters the cell by endocytosis. Virus trafficking was followed at the single-virus level in living cells. The kinetics of virus transport were visualized using fluorescent marker proteins in combination with specific virus labeling. It was found that the virus needs to progress through early and late endosomal compartments in order to efficiently uncoat and release its genome. Further, the virus delays the endosomal acidification to ensure optimal residence time and fusion in the region close to the host cell nucleus. Drug treatment furthermore unraveled critical factors influencing viral infection efficiency.
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Ling, Man-to, and 凌文韜. "The role of mannose binding lectin in influenza virus infection." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2009. http://hub.hku.hk/bib/B43085295.
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Zhang, Naru, and 张娜茹. "Study on influenza virus-like particles and ssDNA aptamers." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2013. http://hdl.handle.net/10722/200167.
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Since there is an urgent need for development of vaccines and antiviral agents to combat influenza pandemics, this study aimed to develop influenza virus-like particles (VLPs) and aptamers targeting the virus particles as vaccine and antiviral agent candidates.
Influenza VLPs containing three structural proteins of hemagglutinin (HA), neuraminidase (NA) and matrix 1 (M1) derived from influenza A/Hong Kong/01/2009 (H1N1) virus (HK/01) were constructed using a Bac-to-Bac baculovirus expression system. The expressed VLPs were purified by sucrose density gradient ultracentrifugation and characterized by Western blotting analysis and transmission electron microscopy. The immune responses and protective efficacy induced by VLPs were compared with those elicited by the clinically used Panenza vaccine in BALB/c mouse model. The results showed that two-dose vaccination with both VLP and the Panenza vaccine could confer complete protection. Single-dose vaccination with VLP could also provide 100% protection against lethal virus challenge, whereas single dose of an equal amount (based on HA content) of the Panenza vaccination just provided incomplete protection (67% survival rate) against the lethal virus challenge. Compared to the Panenza vaccination, the VLP vaccination could induce higher and broader antibody responses and higher viral specific T help (Th) cell and cytotoxic T lymphocyte (CTL) responses. Notably, a novel finding in this study is that the VLP vaccination could induce antibodies to inhibit virus release from infected MDCK cells, although the underlined mechanism needed to be further studied. These results indicated that influenza VLP might be a more effective and safe vaccine candidate which could be developed into an alternative vaccine for the control of epidemic and pandemic influenza in the future.
To develop aptamers as antiviral agents against influenza, I sought to use influenza VLPs as target for ssDNA aptamer selection. After 11 rounds of selection using the systemic evolution of ligandsby exponential enrichment (SELEX),the recovered DNA molecules were PCR-amplified, gel purified and cloned into pCR-Blunt II TOPO vector for sequencing. The sequencing results showed that one aptamer Va-1 was markedly enriched, which was accounted for 59% (13/22) of the selected aptamers. Compared to the other non-enriched aptamers, the enriched aptamer Va-1 showed the highest binding affinity to the UV inactivated influenza HK/01 virus. It was also shown that the aptamer Va-1 specifically bound to the HK/01 stain while it could not bind other respiratory viruses even the PR8 strain within the H1N1 subtype. It was further demonstrated that the aptamer Va-1 could only bind to NA protein in a dose-dependent manner but not bind to HA and M1 proteins. Unfortunately, the selected aptamer did not show any antiviral effects. However, it may be potentially developed into a diagnostic and analytic agent because its binding activity was comparable with that of the commercial anti-NA antibody.
In conclusion, the influenza VLPs may be a promising vaccine candidate for the control of influenza virus infection and the selected aptamer may be potentially developed into an alternative tool for influenza virus detection.published_or_final_version
Microbiology
Doctoral
Doctor of Philosophy
44
Leung, Sze-Yui Horasis, and 梁思睿. "Fibronectin: role in viral cell association, fusion and entry of influenza A virus." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hub.hku.hk/bib/B48329708.
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The influenza A viral hemagglutinin (HA) protein binds to sialic acid (SA) groups of cellular surface glycoproteins to achieve viral attachment and entry. The SA binding specificity of HA is one of the major determinants for controlling viral tropism and host specificity.
Fibronectin (FN) is a ubiquitinious glycoprotein secreted on cell surface, either circulating in plasma, or as one of the best characterized components of the extra cellular matrix. With its binding properties towards different types of molecules and pathogens, it has been utilized by different bacterial and viral pathogens for binding, entry, propagation and pathogenesis. The binding affinity and region of plasma FN to influenza A viral glycoprotein was identified in early 1980s. Evidence also suggests the binding is SA associated. FN associates with different viral pathogens. However, evidence of FN direct involvement in influenza A pathogenesis remains unknown.
The objective of this thesis is to test the involvement of cellular FN in influenza A viral infection. To perform the study, FN siRNA and anti-FN antibody were applied. This study demonstrated possible involvement of FN in the replication of human H1N1 and highly pathogenic avian H5N1 viruses. It also discovered that FN is very important for the replication of H1N1 virus, but not H5N1 virus. Interestingly, the result suggested that FN does not affect the initial virus-host binding, but it has an effect on post-attachment events.
Key amino acid positions controlling the SA binding specificity of seasonal human or avian influenza A viruses have been identified in the HA. In this thesis, reverse genetics and mutagenic work identified that viruses with a α2,3-linked SA (SA α2,3) binding preference were not inhibited by anti-FN antibody, while viruses with a α2,6-linked SA (SA α2,6) specificity were severely inhibited. This surprising finding of SA binding preference related FN involvement in post-attachment event led to the further investigation on the structural involvement of FN and viral entry pathway analysis.
The 9th and 10th of type III repeating units of FN form the cell-binding domain of the protein for cell attachment. From site specific antibody inhibitory studies, the cell binding region of FN near the synergy adhesion site(SAS) and Arg-Gly-Asp-Ser(RGDS) cell adhesion signal was identified to be important for the replication of viruses that have a α2,6 SA binding preference, but it was also found to be independent of α5β1 integrin receptor.
After attaching to a host cell, the virus was internalized in an endosome via clathrin- or caveolin- mediated endocytosis. By application of pathway inhibitors, the FN association with viral entry pathway was evaluated. Though this study failed to identify a single specific FN mediated viral entry pathway, this pathway study indicated the possibility of FN various involvement in influenza viral entry. The study indeed indicated that viruses have difference SA binding preferences are different in their choices in viral entry pathways.
This thesis did not only introduce cellular FN as a novel host factor, but also identified possible target and brought new light in the control of influenza A viral infection.published_or_final_version
Public Health
Doctoral
Doctor of Philosophy
45
Campbell, Gillian Mhairi. "Influenza virus infection in a compromised immune system." Thesis, University of Edinburgh, 2012. http://hdl.handle.net/1842/6521.
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Severe influenza virus infection, including human infection with highly pathogenic H5N1 viruses is characterised by massive pulmonary inflammation, immunopathology and excessive cytokine production, a process in which macrophages may play a vital role. The aim of this project was to investigate the hypothesis that inhibition of inflammatory responses from infected macrophages, using either alternatively activated bone marrow derived macrophages (BMDMf), or IFNg receptor deficient (IFNgR-/-) mice may ameliorate the devastating immunopathology and inflammation routinely observed in highly pathogenic influenza virus infections. Infection of alternatively activated BMDMf resulted in enhanced positivity for viral proteins, compared with classically activated, inflammatory BMDMf. However, neither subset propagated the infection indicating that while infection is abortive in both classical and alternatively activated BMDMf, the latter may prove more efficient at removing infectious virus from the site of infection due to enhanced infectivity. However, influenza virus was capable of driving expression of proinflammatory mediators such as iNOS and TNFa from classical and alternatively activated BMDMf even in the absence of IFNg signalling. IFNgR-/- BMDMf demonstrated a reduced inflammatory response to infection compared to Sv129 counterparts, suggesting a potentially impaired inflammatory response in vivo. This was investigated by infection of IFNgR-/- mice, which resulted in ameliorated disease, lower viral titres and mild immunopathology, demonstrating that inhibition of IFNg signalling limits the severity of disease. Additionally, mRNA expression for key inflammatory mediators was reduced, demonstrating that inhibition of the overwhelming inflammatory response to influenza virus infection is beneficial to the host, resulting in protection from immunopathology and improved prognosis, without impairing viral clearance.
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Ng, Chi-ko, and 伍智高. "Antigenicity and oseltamivir resistance of influenza A virus." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2013. http://hub.hku.hk/bib/B50434536.
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Although several risk factors for severe influenza infection have been identified in previous studies, many patients having multiple risk factors only developed mild symptoms while many healthy young patients developed severe complications when infected with A(H1N1)pdm09. Thus, there are still undiscovered factors that affect the progression and severity of influenza.
The early innate immune response may be critical in determining the disease progression. Non-neutralizing antibodies existed in the early stage of infection may contribute to the outcome of the disease. In this study, the association of disease severity with the titre and avidity of non-neutralizing antibodies in early stage of influenza infection was investigated. It has been shown that the titre of non-neutralizing antibody was higher in more severe patients in the early stage of infection. Higher antibody avidity was also found to be associated with more severe disease independently. These findings tend to support the view that antigenic drift leads to an excessive production of pro-inflammatory non-neutralizing antibodies in the patients and associated with severe outcome.
Since patients with more severe disease tend to have a delayed clearance of the virus and allow more transmission, the antigenically shifted or drifted influenza virus may gradually become predominant in human population. This idea suggested that the predominance of influenza virus with NA-H275Y mutation in 2007-2008 was contributed by the co-existing, fitness restoring secondary adaptive mutation in HA. NA-H275Y was identified in previous studies to be the mutation encoding for the influenza virus to resist against oseltamivir but would also change the property of NA as a result of compromised viral fitness. Therefore, influenza virus carrying NA-H275Y is unlikely to emerge and spread in human population. However, NA-H275Y mutated strains of influenza virus emerged and spread globally in the influenza season of 2007-2008 and quickly become the predominant strain in 2008. Previous study found NA-R222Q and NA-V234M were the mutations responsible for restoring the viral fitness in oseltamivir resistant clinical isolates. Still, this cannot fully explain the predominance of the resistant strains over the susceptible strains. Therefore secondary adaptive mutation in HA was believed to be present and cause antigenic change to the resistant strains of influenza. In this study, mutual information analysis and HA structural analysis were conducted to screen out HA-A189T and HA-Y94H to be the candidates co-exist with NA-H275Y and possibly critical for antigenic changes. This study further suggested that HA-Y94H mutation leads to a change of antigenic property of the virus by examining the antigenicity and growth kinetics of the recombinant viruses carrying the selected HA mutations. HA-94 may be critical for determining both the receptor binding property and antigenic property of the virus. Review on the evolution of seasonal influenza viruses from 2005 to 2008 suggested that the emergence of HA-Y94H mutation may enhance the presence of NA-H275Y and helps the viruses carrying NA-H275Y to spread and dominate over the oseltamivir susceptible strains during 2007 and 2008.published_or_final_version
Microbiology
Master
Master of Philosophy
47
Mahallawi, Waleed. "Natural immunity to influenza virus in humans following 2009 pandemic H1N1 influenza." Thesis, University of Liverpool, 2013. http://livrepository.liverpool.ac.uk/13137/.
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Influenza is a highly contagious and acute respiratory infection caused by influenza virus in the mucosa of the respiratory tract. Both seasonal and pandemic influenza continue to cause substantial morbidity and mortality in humans. The 2009 pandemic H1N1 (pH1N1) influenza and the potential of a highly pathogenic avian H5N1 (aH5N1) pandemic highlighted the need for effective preventative strategies. Understanding the development of natural immunity following the pH1N1 pandemic may provide important information on host protective immunity in humans, which could inform future more effective vaccination strategies against influenza. In this thesis, naturally developed mucosal immunity to 2009 pH1N1 virus was studied in children and adults using cells derived from human nasal-associated lymphoid tissue (NALT). Firstly, the frequency of HA-specific memory B cells in human NALT to pH1N1 virus and their ability to produce cross-reactive antibodies were studied. Patients who had serological evidence of previous exposure to pH1N1 virus developed large numbers of IgG memory B cells in NALT that produce crossreactive neutralizing antibodies against a number of influenza subtypes upon pH1N1 virus antigen stimulation. The presence of such memory B cells in human NALT appears to have primed the host for cross-reactive mucosal memory response against other H1N1 and the highly pathogenic aH5N1 virus strains. These findings may have important implications in future vaccination strategies against influenza. Secondly, serum specific anti-pH1N1 HA IgG antibodies were analysed using ELISA. HA-specific antibody levels to pH1N1 in adults were significantly higher than that of children. The results may suggest that adults had been exposed to more cross-reactive influenza viruses than children, and developed more cross-reactive memory responses against some influenza viruses than in children. Significantly higher HA-specific IgG antibody titres to pH1N1 HA (measured using ELISA) were found in subjects who had HAI titres≥40 than in those with HAI antibody titre<40. This suggests that following the 2009 pH1N1 pandemics, large numbers of people developed anti-pH1N1 HA antibodies to both the circular head and the stalk regions of HA which may have broader protective immunity. Thirdly, HA-specific memory CD4+ T cell response to pH1N1 virus was shown in tonsillar cells from children and adults. This suggests that following the 2009 pandemic H1N1 influenza, humans developed memory T cell response to the pH1N1 HA protein antigen at the mucosal level in the nasopharynx. There appeared to be an age-associated increase in this memory response. Finally, mucosal antibody responses in NALT to HAs of a number of influenza A viruses were investigated following in vitro stimulation of adenotonsillar cells with LAIV vaccine which contains a 2009 pandemic H1N1 virus, a seasonal H3N2 and a B influenza strain. Significant antibody responses of all 3 isotypes (IgG, IgA and IgM) to the HA of pandemic H1N1 virus were observed in tonsillar cells following LAIV stimulation. It suggests that the in vitro model of human NALT using adenotonsillar cell culture could be used to study the LAIV-induced immune responses which may predict the immunogenicity and efficacy of candidate LAIV vaccines in humans.
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Killian, Mary Lea. "Identification and characterization of H2N3 avian influenza virus from backyard poultry and comparison to novel H2N3 swine influenza virus." [Ames, Iowa : Iowa State University], 2009.
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Ling, Man-to, and 凌文韜. "The role of mannose binding lectin in pandemic H1N1 influenza virus infection." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hub.hku.hk/bib/B50567214.
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Perera, Kumarapatti Vidanalage Harsha Kumara Kithsiri. "Ecology and evolution of swine influenza virus in Sri Lanka." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2013. http://hdl.handle.net/10722/196456.
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Influenza A virus infections in pigs is a disease of concern to the swine industry and to the ecology and epidemiology of influenza viruses in humans. Pigs have been proposed as a “mixing vessel” for generation of pandemics via reassortment between avian and mammalian viruses. The H1N1pdm 2009 virus probably emerged from swine into humans though reassortment between the recent North American triple reassortant H1N2 swine viruses and Eurasian avian-like swine viruses.
Swine influenza viruses of H1N1, H1N2 and H3N2 subtypes have been regularly detected in pigs in most parts of the world. Nevertheless, ecological and virological data on swine influenza is not available in Sri Lanka, and indeed, little documented data is available in the South Asian continent. The swine population in Sri Lanka is about 80,000, and live pigs are not regularly imported to the country. Swine husbandry is largely confined to four neighboring administrative districts in the country.
Systematic virological and serological surveillance carried in swine abattoirs in Sri Lanka during 2009-2013 detected H1N1pdm 2009 like virus in local herds. Infection in pigs followed each of the H1N1pdm 2009 outbreaks in humans; October 2009 – January 2010, October 2010 – February 2011 and November 2012 – March 2013, respectively. Genetic, phylogenetic, and epidemiologic analysis of the human, and swine influenza viruses indicated spillover events of H1N1pdm 2009 from humans into pigs, with self-limited transmission and extinction within pig herds. The data also indicated that although H1N1pdm 2009 was able to spill over from humans to swine, it is not ideally adapted to establish sustained transmission among swine in the absence of further reassortment with other swine influenza virus lineages.
Theses finding might reflect characteristics of swine husbandry in Sri Lanka, which has a low density pig population and remains isolated from global swine influenza viruses because of the absence of regular cross-border and cross-continental movements of swine. In contrast to some other parts of the world, we failed to isolate established lineages of swine influenza viruses, viz. Classical, North American triple reassortant and European Avian lineages. Sero prevalence to these endemic swine viruses was largely absent in local swine herds.
In vitro replicative kinetic study indicated that H1N1pdm 2009 viruses isolated from swine have undergone some adaptation to swine led to decreased fitness for replication in human cells.published_or_final_version
Public Health
Doctoral
Doctor of Philosophy