39 results on '"Gillan, Victoria"'
Search Results
2. Ivermectin – Old Drug, New Tricks?
- Author
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Laing, Roz, Gillan, Victoria, and Devaney, Eileen
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- 2017
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3. Regulation of immune responses by the L3 of Brugia pahangi
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Gillan, Victoria Ann
- Subjects
571.9991 - Abstract
Lymphatic filarial worms are mosquito borne parasites which cause chronic disease in humans. Infection is characterized by proliferative suppression of T cells in the host and a skewing of the immune response, away from an IFN-gamma producing Th1 response, towards a Th2 or regulatory phenotype, with production of IL-4 and IL-10. In this study, a mouse model was used to investigate the role of the infective form of the parasite (the third stage larvae, L3) in regulating immune responses. BALB/c mice were infected by the subcutaneous route to mimic the natural transmission of the parasite, and immune responses generated by the L3 were analysed. Experiments carried out in the intact BALB/c mouse showed that infection with L3 results in increased IL-4, IL-10 and IL-5 with no IL-2 or IFN-gamma, a similar situation to that observed in infected humans. In order to investigate the key components in this skewing of the immune response, experiments were carried out using IL-4-/- mice. IL-4 was shown to have a role in down-regulating Th1 responses in wild type mice, as knock-out animals produced elevated levels of IL-2 and IFN-gamma. However these mice still had the capacity to produce IL-5, IL-13 and IL-10, suggesting that although IL-4 is an important Th2 cytokine, it may be dispensable in the initiation of such a response. In addition, reduced levels of proliferation of CD4+ and B220+ cells were observed in infected IL-4-/- mice. Despite elevated levels of IFN-gamma, this reduction in proliferation was not associated with increased production of NO, and neutralizing IFN-gamma itself did not restore proliferative responses. Addition of rIL-4 to cultures of splenocytes from these mice had a mild effect but did not result in a significant increase in proliferation. Treatment of splenocytes from intact mice with anti-IL-10 MAb in vitro resulted in increased levels of IL-2 and IFN-gamma, but no significant effect on Ag-specific proliferation was observed. However, when mice were treated with an anti-IL-10R MAb the opposite effect was seen, with a significant increase in levels of proliferation and no alteration in cytokines. When examined by FACS it was shown that CD4+ cells were the major population which expanded during IL-10R blockade. In addition, CD4+ cells were found to be the major source of IL-10 post-infection with L3, suggesting these cells may modulate their own proliferation, or perhaps these cells were of a regulatory nature. Experiments were also carried out to determine the effect of natural transmission on host immune responses. L3 were administered via syringe inoculation or via mosquito transmission. Splenocytes from mice infected via syringe inoculation had an increased capacity to produce cytokines and displayed higher levels of proliferation. Further experiments demonstrated that cytokine and proliferative responses were not dose- dependant therefore there may be factors within mosquito saliva which down-regulate immune responses in the mouse model.
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- 2004
4. Profiling microRNAs through development of the parasitic nematode Haemonchus identifies nematode-specific miRNAs that suppress larval development
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Marks, Neil D., Winter, Alan D., Gu, Henry Y., Maitland, Kirsty, Gillan, Victoria, Ambroz, Martin, Martinelli, Axel, Laing, Roz, MacLellan, Rachel, Towne, Jessica, Roberts, Brett, Hanks, Eve, Devaney, Eileen, and Britton, Collette
- Published
- 2019
- Full Text
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5. Parasitic nematode miRNAs and EVs - transfection into organoid epithelial cells
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Perez, Matias Gaston, Gillan, Victoria, Devaney, Eileen, and Britton, Collette
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- 2023
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- View/download PDF
6. Application of small RNA technology for improved control of parasitic helminths
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Britton, Collette, Winter, Alan D., Marks, Neil D., Gu, Henry, McNeilly, Tom N., Gillan, Victoria, and Devaney, Eileen
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- 2015
- Full Text
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7. microRNAs of parasitic helminths – Identification, characterization and potential as drug targets
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Britton, Collette, Winter, Alan D., Gillan, Victoria, and Devaney, Eileen
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- 2014
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8. microRNAs in gastrointestinal nematode-host interactions
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Perez, Matias Gaston, Gillan, Victoria, Maitland, Kirsty, Devaney, Eileen, and Britton, Collette
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- 2022
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9. Tuft Cells Increase Following Ovine Intestinal Parasite Infections and Define Evolutionarily Conserved and Divergent Responses
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Hildersley, Katie A., primary, McNeilly, Tom N., additional, Gillan, Victoria, additional, Otto, Thomas D., additional, Löser, Stephan, additional, Gerbe, François, additional, Jay, Philippe, additional, Maizels, Rick M., additional, Devaney, Eileen, additional, and Britton, Collette, additional
- Published
- 2021
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10. Functional genomics of hsp-90 in parasitic and free-living nematodes
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Gillan, Victoria, Maitland, Kirsty, McCormack, Gillian, Nik Him, Nik A.I.I., and Devaney, Eileen
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- 2009
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11. Nematode Hsp90: highly conserved but functionally diverse
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GILLAN, VICTORIA and DEVANEY, EILEEN
- Published
- 2014
12. Characterisation of infection associated microRNA and protein cargo in extracellular vesicles of Theileria annulata infected leukocytes
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Gillan, Victoria, Simpson, Deborah M., Kinnaird, Jane, Maitland, Kirsty, Shiels, Brian, and Devaney, Eileen
- Abstract
The protozoan parasites, Theileria annulata and T. parva are unique amongst intracellular eukaryotic pathogens as they induce a transformation‐like phenotype in their bovine host cell. T. annulata causes tropical theileriosis, which is frequently fatal, with infected leukocytes becoming metastatic and forming foci in multiple organs resulting in destruction of the lymphoid system. Exosomes, a sub‐set of extracellular vesicles (EV), are critical in metastatic progression in many cancers. Here we characterised the cargo of EV from a control bovine lymphosarcoma cell line (BL20) and BL20 infected with T. annulata (TBL20) by comparative mass spectrometry and miRNA profiling (data available via ProteomeXchange, identifier PXD010713 and NCBI GEO, accession number GSE118456, respectively). Ingenuity Pathway Analysis that many infection‐associated proteins essential to migration and extracellular matrix digestion were upregulated in EV from TBL20 cells compared to BL20 controls. An altered repertoire of host miRNA, many with known roles in tumor and/or infection biology was also observed. Focusing on the tumor suppressor miRNA, bta‐miR‐181a and bta‐miR‐181b, we identified putative mRNA targets and confirmed the interaction of bta‐miR181a with icam‐1. We propose that EV and their miRNA cargo play an important role in the manipulation of the host cell phenotype and the pathobiology of Theileria infection.
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- 2019
13. B cells play a regulatory role in mice infected with the L3 of Brugia pahangi
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Gillan, Victoria, Lawrence, Rachel A., and Devaney, Eileen
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- 2005
14. Mosquito transmission modulates the immune response in mice infected with the L3 of Brugia pahangi
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GILLAN, VICTORIA and DEVANEY, EILEEN
- Published
- 2004
15. Increased Expression of a MicroRNA Correlates with Anthelmintic Resistance in Parasitic Nematodes
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Gillan, Victoria, Maitland, Kirsty, Laing, Roz, Gu, Henry, Marks, Neil D., Winter, Alan D., Bartley, David, Morrison, Alison, Skuce, Philip J., Rezansoff, Andrew M., Gilleard, John S., Martinelli, Axel, Britton, Collette, and Devaney, Eileen
- Subjects
Microbiology (medical) ,Anthelmintics ,drug resistance ,Ivermectin ,microRNA ,Nematoda ,Immunology ,lcsh:QR1-502 ,Gene Expression ,Microbiology ,lcsh:Microbiology ,MicroRNAs ,Infectious Diseases ,HEK293 Cells ,parasitic diseases ,Animals ,Humans ,Haemonchus ,Female ,RNA, Messenger ,Biomarkers ,Original Research ,parasitic nematode - Abstract
Resistance to anthelmintic drugs is a major problem in the global fight against parasitic nematodes infecting humans and animals. While previous studies have identified mutations in drug target genes in resistant parasites, changes in the expression levels of both targets and transporters have also been reported. The mechanisms underlying these changes in gene expression are unresolved. Here, we take a novel approach to this problem by investigating the role of small regulatory RNAs in drug resistant strains of the important parasite Haemonchus contortus. microRNAs (miRNAs) are small (22 nt) non-coding RNAs that regulate gene expression by binding predominantly to the 3′ UTR of mRNAs. Changes in miRNA expression have been implicated in drug resistance in a variety of tumor cells. In this study, we focused on two geographically distinct ivermectin resistant strains of H. contortus and two lines generated by multiple rounds of backcrossing between susceptible and resistant parents, with ivermectin selection. All four resistant strains showed significantly increased expression of a single miRNA, hco-miR-9551, compared to the susceptible strain. This same miRNA is also upregulated in a multi-drug-resistant strain of the related nematode Teladorsagia circumcincta. hco-miR-9551 is enriched in female worms, is likely to be located on the X chromosome and is restricted to clade V parasitic nematodes. Genes containing predicted binding sites for hco-miR-9551 were identified computationally and refined based on differential expression in a transcriptomic dataset prepared from the same drug resistant and susceptible strains. This analysis identified three putative target mRNAs, one of which, a CHAC domain containing protein, is located in a region of the H. contortus genome introgressed from the resistant parent. hco-miR-9551 was shown to interact with the 3′ UTR of this gene by dual luciferase assay. This study is the first to suggest a role for miRNAs and the genes they regulate in drug resistant parasitic nematodes. miR-9551 also has potential as a biomarker of resistance in different nematode species.
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- 2017
16. Characterisation of infection associated microRNA and protein cargo in extracellular vesicles ofTheileria annulatainfected leukocytes
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Gillan, Victoria, primary, Simpson, Deborah M., additional, Kinnaird, Jane, additional, Maitland, Kirsty, additional, Shiels, Brian, additional, and Devaney, Eileen, additional
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- 2018
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17. Hsp-90 and the biology of nematodes
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Maitland Kirsty, Emes Richard D, Gillan Victoria, Him Nik AIIN, and Devaney Eileen
- Subjects
Evolution ,QH359-425 - Abstract
Abstract Background Hsp-90 from the free-living nematode Caenorhabditis elegans is unique in that it fails to bind to the specific Hsp-90 inhibitor, geldanamycin (GA). Here we surveyed 24 different free-living or parasitic nematodes with the aim of determining whether C. elegans Hsp-90 was the exception or the norm amongst the nematodes. We combined these data with codon evolution models in an attempt to identify whether hsp-90 from GA-binding and non-binding species has evolved under different evolutionary constraints. Results We show that GA-binding is associated with life history: free-living nematodes and those parasitic species with free-living larval stages failed to bind GA. In contrast, obligate parasites and those worms in which the free-living stage in the environment is enclosed within a resistant egg, possess a GA-binding Hsp-90. We analysed Hsp-90 sequences from fifteen nematode species to determine whether nematode hsp-90s have undergone adaptive evolution that influences GA-binding. Our data provide evidence of rapid diversifying selection in the evolution of the hsp-90 gene along three separate lineages, and identified a number of residues showing significant evidence of adaptive evolution. However, we were unable to prove that the selection observed is correlated with the ability to bind geldanamycin or not. Conclusion Hsp-90 is a multi-functional protein and the rapid evolution of the hsp-90 gene presumably correlates with other key cellular functions. Factors other than primary amino acid sequence may influence the ability of Hsp-90 to bind to geldanamycin.
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- 2009
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18. Characterization of HSP90 isoforms in transformed bovine leukocytes infected with Theileria annulata
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Kinnaird, Jane H., Singh, Meetali, Gillan, Victoria, Weir, William, Calder, Ewen D.D., Hostettler, Isabel, Tatu, Utpal, Devaney, Eileen, and Shiels, Brian R.
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EXPRESSION ,SHOCK-PROTEIN 90 ,GRP94 ,Microbiology ,Biochemistry ,ACTIVATION ,HEAT-SHOCK-PROTEIN-90 ,1108 Medical Microbiology ,Leukocytes ,polycyclic compounds ,Animals ,Protein Isoforms ,HSP90 Heat-Shock Proteins ,IKK SIGNALOSOMES ,PARASITE ,Cells, Cultured ,Organelles ,MOLECULAR CHAPERONE ,Science & Technology ,DRUG TARGET ,Cell Biology ,Theileria annulata ,Cattle ,HOST-CELL ,Life Sciences & Biomedicine ,0605 Microbiology - Abstract
HSP90 chaperones are essential regulators of cellular function, as they ensure the appropriate conformation of multiple key client proteins. Four HSP90 isoforms were identified in the protozoan parasite Theileria annulata. Partial characterization was undertaken for three and localization confirmed for cytoplasmic (TA12105), endoplasmic reticulum (TA06470), and apicoplast (TA10720) forms. ATPase activity and binding to the HSP90 inhibitor geldanamycin were demonstrated for recombinant TA12105, and all three native forms could be isolated to varying extents by binding to geldanamycin beads. Because it is essential, HSP90 is considered a potential therapeutic drug target. Resistance to the only specific Theileriacidal drug is increasing, and one challenge for design of drugs that target the parasite is to limit the effect on the host. An in vitro cell culture system that allows comparison between uninfected bovine cells and the T. annulata‐infected counterpart was utilized to test the effects of geldanamycin and the derivative 17‐AAG. T. annulata‐infected cells had greater tolerance to geldanamycin than uninfected cells yet exhibited significantly more sensitivity to 17‐AAG. These findings suggest that parasite HSP90 isoform(s) can alter the drug sensitivity of infected host cells and that members of the Theileria HSP90 family are potential targets worthy of further investigation.
- Published
- 2017
19. Characterization of HSP90 isoforms in transformed bovine leukocytes infected withTheileria annulata
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Kinnaird, Jane H., primary, Singh, Meetali, additional, Gillan, Victoria, additional, Weir, William, additional, Calder, Ewen D. D., additional, Hostettler, Isabel, additional, Tatu, Utpal, additional, Devaney, Eileen, additional, and Shiels, Brian R., additional
- Published
- 2016
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20. A repurposing strategy for Hsp90 inhibitors demonstrates\ud their potency against filarial nematodes
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Gillan, Victoria, O’Neill, Kerry, Maitland, Kirsty, Sverdrup, Francis M., and Devaney, Eileen
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fungi ,parasitic diseases - Abstract
Novel drugs are required for the elimination of infections caused by filarial worms, as most commonly used drugs largely target the microfilariae or first stage larvae of these infections. Previous studies, conducted in vitro, have shown that inhibition of Hsp90 kills adult Brugia pahangi. As numerous small molecule inhibitors of Hsp90 have been developed for use in cancer chemotherapy, we tested the activity of several novel Hsp90 inhibitors in a fluorescence polarization assay and against microfilariae and adult worms of Brugia in vitro. The results from all three assays correlated reasonably well and one particular compound, NVP-AUY922, was shown to be particularly active, inhibiting Mf output from female worms at concentrations as low as 5.0 nanomolar after 6 days exposure to drug. NVP-AUY922 was also active on adult worms after a short 24 h exposure to drug. Based on these in vitro data, NVP-AUY922 was tested in vivo in a mouse model and was shown to significantly reduce the recovery of both adult worms and microfilariae. These studies provide proof of principle that the repurposing of currently available Hsp90 inhibitors may have potential for the development of novel agents with macrofilaricidal properties.
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- 2014
21. Hsp90 Inhibitors in Parasitic Nematodes: Prospects and Challenges
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Devaney, Eileen, primary and Gillan, Victoria, additional
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- 2016
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22. A novel member of the let-7 microRNA family is associated with developmental transitions in filarial nematode parasites
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Winter, Alan D, primary, Gillan, Victoria, additional, Maitland, Kirsty, additional, Emes, Richard D, additional, Roberts, Brett, additional, McCormack, Gillian, additional, Weir, William, additional, Protasio, Anna V, additional, Holroyd, Nancy, additional, Berriman, Matthew, additional, Britton, Collette, additional, and Devaney, Eileen, additional
- Published
- 2015
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23. Assay Strategies for the Discovery and Validation of Therapeutics Targeting Brugia pahangi Hsp90
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Taldone, Tony, primary, Gillan, Victoria, additional, Sun, Weilin, additional, Rodina, Anna, additional, Patel, Pallav, additional, Maitland, Kirsty, additional, O'Neill, Kerry, additional, Chiosis, Gabriela, additional, and Devaney, Eileen, additional
- Published
- 2010
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24. Hsp-90 and the biology of nematodes
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Him, Nik AIIN, primary, Gillan, Victoria, additional, Emes, Richard D, additional, Maitland, Kirsty, additional, and Devaney, Eileen, additional
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- 2009
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25. The E6E7 oncoproteins of cutaneous human papillomavirus type 38 interfere with the interferon pathway
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Cordano, Pablo, primary, Gillan, Victoria, additional, Bratlie, Sigrid, additional, Bouvard, Veronique, additional, Banks, Lawrence, additional, Tommasino, Massimo, additional, and Campo, M. Saveria, additional
- Published
- 2008
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26. Regulatory T Cells Modulate Th2 Responses Induced byBrugia pahangiThird-Stage Larvae
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Gillan, Victoria, primary and Devaney, Eileen, additional
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- 2005
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27. Interleukin-4 influences the production of microfilariae in a mouse model of Brugia infection
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Devaney, Eileen, primary, Gillan, Victoria, additional, Wheatley, Isla, additional, Jenson, Jessica, additional, O'Connor, Richard, additional, and Balmer, Paul, additional
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- 2002
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28. Mosquito transmission modulates the immune response in mice infected with the L3 ofBrugia pahangi.
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Gillan, Victoria and Devaney, Eileen
- Subjects
- *
FILARIAL worms , *MOSQUITOES , *IMMUNOSUPPRESSION , *ANTIGENS , *IMMUNE response , *CELLS - Abstract
Mice infected by syringe inoculation with the L3 of the filarial nematodeBrugia pahangigenerate a strong Th2 response. In this study we compared immune responses in mice infected via syringe with those infected by mosquito transmission of L3. Levels of antigen-specific IL-4, IL-5 and IL-10 were significantly reduced in mice infected via mosquito. A possible explanation of these results was that mice infected via mosquito received fewer L3 than those infected via syringe. To investigate this possibility, mice were infected with different numbers of L3 (50, 25 or 10). Howere there was no difference in responses in these animals, suggesting that the reduced immune reactivity in mice infected by mosquito cannot be solely ascribed to exposure to lower numbers of parasites. These results also demonstrate that the L3 is an extremely potent stimulus for Th2 differentiation, with 10 L3 sufficient to drive a strong Th2 response. The differences in immune reactivity between syringe and mosquito infected mice may relate to the presence of immuno-suppressive factors in mosquito saliva inoculated at the time of transmission or may reflect the interaction of L3 with different populations of antigen presenting cells in the two groups of mice. Further studies will be required to differentiate between these possibilities. [ABSTRACT FROM AUTHOR]
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- 2004
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29. Regulatory T Cells Modulate Th2 Responses Induced by Brugia pahangi Third-Stage Larvae
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Gillan, Victoria and Devaney, Eileen
- Abstract
Infection of BALB/c mice with Brugia pahangi third-stage larvae (L3) results in the production of interleukin-4 (IL-4), IL-5, and IL-10 with a resultant down-regulation in Th1 responses. Previously, this was thought to reflect a skewing of immune responses towards a Th2 phenotype by the infective stage of the parasite. In this study, we show that exposure to the L3 of Brugia also induces the expansion of a population of CD4 cells that express CD25 and cytotoxic-T-lymphocyte-associated antigen 4 in an IL-4-independent fashion. By quantitative reverse transcription-PCR, we show that the CD25+ population is highly enriched in mRNA for the Foxp3 transcription factor and that these cells express significantly more IL-10 mRNA than the CD25– population, suggesting a likely regulatory phenotype. The functional capacity of these cells was demonstrated using a neutralizing CD25 monoclonal antibody (MAb). Mice treated with this MAb demonstrated elevated levels of antigen (Ag)-specific proliferation in vitro, and levels of Ag-specific Th2 cytokines were significantly increased. These results suggest a complex network of regulation in L3-infected mice with Th2 cells limiting the Th1 response, while T-regulatory cells modulate Th2 responses.
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- 2005
30. Regulatory T Cells Modulate Th2 Responses Induced by Brugia pahangiThird-Stage Larvae
- Author
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Gillan, Victoria and Devaney, Eileen
- Abstract
ABSTRACTInfection of BALB/c mice with Brugia pahangithird-stage larvae (L3) results in the production of interleukin-4 (IL-4), IL-5, and IL-10 with a resultant down-regulation in Th1 responses. Previously, this was thought to reflect a skewing of immune responses towards a Th2 phenotype by the infective stage of the parasite. In this study, we show that exposure to the L3 of Brugiaalso induces the expansion of a population of CD4 cells that express CD25 and cytotoxic-T-lymphocyte-associated antigen 4 in an IL-4-independent fashion. By quantitative reverse transcription-PCR, we show that the CD25+population is highly enriched in mRNA for the Foxp3transcription factor and that these cells express significantly more IL-10mRNA than the CD25−population, suggesting a likely regulatory phenotype. The functional capacity of these cells was demonstrated using a neutralizing CD25 monoclonal antibody (MAb). Mice treated with this MAb demonstrated elevated levels of antigen (Ag)-specific proliferation in vitro, and levels of Ag-specific Th2 cytokines were significantly increased. These results suggest a complex network of regulation in L3-infected mice with Th2 cells limiting the Th1 response, while T-regulatory cells modulate Th2 responses.
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- 2005
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31. Application of small RNA technology for improved control of parasitic helminths
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Britton, Collette, Winter, Alan D., Marks, Neil D., Gu, Henry, McNeilly, Tom N., Gillan, Victoria, and Devaney, Eileen
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MicroRNA ,veterinary(all) ,Article ,Host-Parasite Interactions ,Gene regulation ,MicroRNAs ,RNA interference ,Gene Expression Regulation ,Helminths ,Diagnosis ,Helminth ,Animals ,Parasitology ,Helminthiasis, Animal ,RNA, Small Interfering ,ComputingMethodologies_COMPUTERGRAPHICS ,Nematode - Abstract
Graphical abstract, Highlights • MicroRNAs and siRNAs in helminth post-transcriptional gene regulation are reviewed. • Many parasitic helminth miRNAs are unique and developmentally expressed. • miRNAs released by parasites have diagnostic potential, particularly for filarial and schistosome spp. • Parasite and host miRNAs may regulate immune responses. • Improvements to siRNA-mediated gene silencing are important for functional genomics., Over the last decade microRNAs (miRNAs) and small interfering RNAs (siRNAs) have emerged as important regulators of post-transcriptional gene expression. miRNAs are short, non-coding RNAs that regulate a variety of processes including cancer, organ development and immune function. This class of small RNAs bind with partial complementarity to their target mRNA sequences, most often in the 3′UTR, to negatively regulate gene expression. In parasitic helminths, miRNAs are being increasingly studied for their potential roles in development and host-parasite interactions. The availability of genome data, combined with small RNA sequencing, has paved the way to profile miRNAs expressed at particular developmental stages for many parasitic helminths. While some miRNAs are conserved across species, others appear to be unique to specific parasites, suggesting important roles in adaptation and survival in the host environment. Some miRNAs are released from parasites, in exosomes or in protein complexes, and the potential effects of these on host immune function are being increasingly studied. In addition, release of miRNAs from schistosome and filarial parasites into host plasma can be exploited for the development of specific and sensitive diagnostic biomarkers of infection. Interfering with miRNA function, as well as silencing key components of the pathways they regulate, will progress our understanding of parasite development and provide a novel approach to therapeutic control. RNA interference (RNAi) by siRNAs has proven to be inconsistent in parasitic nematodes. However, the recent successes reported for schistosome and liver fluke RNAi, encourage further efforts to enhance delivery of RNA and improve in vitro culture systems and assays to monitor phenotypic effects in nematodes. These improvements are important for the establishment of reliable functional genomic platforms for novel drug and vaccine development. In this review we focus on the important roles of miRNAs and siRNAs in post-transcriptional gene regulation in veterinary parasitic helminths and the potential value of these in parasite diagnosis and control.
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32. A novel member of the let-7 microRNA family is associated with developmental transitions in filarial nematode parasites
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Winter, Alan D., Gillan, Victoria, Maitland, Kirsty, Emes, Richard D., Roberts, BBrett, McCormack, Gillian, Weir, William, Prostaio, Anna V., Holroyd, Nancy, Berriman, Matthew, Britton, Collette, Devaney, Eileen, Winter, Alan D., Gillan, Victoria, Maitland, Kirsty, Emes, Richard D., Roberts, BBrett, McCormack, Gillian, Weir, William, Prostaio, Anna V., Holroyd, Nancy, Berriman, Matthew, Britton, Collette, and Devaney, Eileen
- Abstract
Background: Filarial nematodes are important pathogens in the tropics transmitted to humans via the bite of blood sucking arthropod vectors. The molecular mechanisms underpinning survival and differentiation of these parasites following transmission are poorly understood. microRNAs are small non-coding RNA molecules that regulate target mRNAs and we set out to investigate whether they play a role in the infection event. Results: microRNAs differentially expressed during the early post-infective stages of Brugia pahangi L3 were identified by microarray analysis. One of these, bpa-miR-5364, was selected for further study as it is upregulated ~12-fold at 24 hours post-infection, is specific to clade III nematodes, and is a novel member of the let-7 family, which are known to have key developmental functions in the free-living nematode Caenorhabditis elegans. Predicted mRNA targets of bpa-miR-5364 were identified using bioinformatics and comparative genomics approaches that relied on the conservation of miR-5364 binding sites in the orthologous mRNAs of other filarial nematodes. Finally, we confirmed the interaction between bpa-miR-5364 and three of its predicted targets using a dual luciferase assay. Conclusions: These data provide new insight into the molecular mechanisms underpinning the transmission of third stage larvae of filarial nematodes from vector to mammal. This study is the first to identify parasitic nematode mRNAs that are verified targets of specific microRNAs and demonstrates that post-transcriptional control of gene expression via stage-specific expression of microRNAs may be important in the success of filarial infection.
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33. A novel member of the let-7 microRNA family is associated with developmental transitions in filarial nematode parasites
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Winter, Alan D., Gillan, Victoria, Maitland, Kirsty, Emes, Richard D., Roberts, BBrett, McCormack, Gillian, Weir, William, Prostaio, Anna V., Holroyd, Nancy, Berriman, Matthew, Britton, Collette, Devaney, Eileen, Winter, Alan D., Gillan, Victoria, Maitland, Kirsty, Emes, Richard D., Roberts, BBrett, McCormack, Gillian, Weir, William, Prostaio, Anna V., Holroyd, Nancy, Berriman, Matthew, Britton, Collette, and Devaney, Eileen
- Abstract
Background: Filarial nematodes are important pathogens in the tropics transmitted to humans via the bite of blood sucking arthropod vectors. The molecular mechanisms underpinning survival and differentiation of these parasites following transmission are poorly understood. microRNAs are small non-coding RNA molecules that regulate target mRNAs and we set out to investigate whether they play a role in the infection event. Results: microRNAs differentially expressed during the early post-infective stages of Brugia pahangi L3 were identified by microarray analysis. One of these, bpa-miR-5364, was selected for further study as it is upregulated ~12-fold at 24 hours post-infection, is specific to clade III nematodes, and is a novel member of the let-7 family, which are known to have key developmental functions in the free-living nematode Caenorhabditis elegans. Predicted mRNA targets of bpa-miR-5364 were identified using bioinformatics and comparative genomics approaches that relied on the conservation of miR-5364 binding sites in the orthologous mRNAs of other filarial nematodes. Finally, we confirmed the interaction between bpa-miR-5364 and three of its predicted targets using a dual luciferase assay. Conclusions: These data provide new insight into the molecular mechanisms underpinning the transmission of third stage larvae of filarial nematodes from vector to mammal. This study is the first to identify parasitic nematode mRNAs that are verified targets of specific microRNAs and demonstrates that post-transcriptional control of gene expression via stage-specific expression of microRNAs may be important in the success of filarial infection.
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- View/download PDF
34. A novel member of the let-7 microRNA family is associated with developmental transitions in filarial nematode parasites
- Author
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Winter, Alan D., Gillan, Victoria, Maitland, Kirsty, Emes, Richard D., Roberts, BBrett, McCormack, Gillian, Weir, William, Prostaio, Anna V., Holroyd, Nancy, Berriman, Matthew, Britton, Collette, Devaney, Eileen, Winter, Alan D., Gillan, Victoria, Maitland, Kirsty, Emes, Richard D., Roberts, BBrett, McCormack, Gillian, Weir, William, Prostaio, Anna V., Holroyd, Nancy, Berriman, Matthew, Britton, Collette, and Devaney, Eileen
- Abstract
Background: Filarial nematodes are important pathogens in the tropics transmitted to humans via the bite of blood sucking arthropod vectors. The molecular mechanisms underpinning survival and differentiation of these parasites following transmission are poorly understood. microRNAs are small non-coding RNA molecules that regulate target mRNAs and we set out to investigate whether they play a role in the infection event. Results: microRNAs differentially expressed during the early post-infective stages of Brugia pahangi L3 were identified by microarray analysis. One of these, bpa-miR-5364, was selected for further study as it is upregulated ~12-fold at 24 hours post-infection, is specific to clade III nematodes, and is a novel member of the let-7 family, which are known to have key developmental functions in the free-living nematode Caenorhabditis elegans. Predicted mRNA targets of bpa-miR-5364 were identified using bioinformatics and comparative genomics approaches that relied on the conservation of miR-5364 binding sites in the orthologous mRNAs of other filarial nematodes. Finally, we confirmed the interaction between bpa-miR-5364 and three of its predicted targets using a dual luciferase assay. Conclusions: These data provide new insight into the molecular mechanisms underpinning the transmission of third stage larvae of filarial nematodes from vector to mammal. This study is the first to identify parasitic nematode mRNAs that are verified targets of specific microRNAs and demonstrates that post-transcriptional control of gene expression via stage-specific expression of microRNAs may be important in the success of filarial infection.
- Full Text
- View/download PDF
35. A novel member of the let-7 microRNA family is associated with developmental transitions in filarial nematode parasites
- Author
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Winter, Alan D., Gillan, Victoria, Maitland, Kirsty, Emes, Richard D., Roberts, BBrett, McCormack, Gillian, Weir, William, Prostaio, Anna V., Holroyd, Nancy, Berriman, Matthew, Britton, Collette, Devaney, Eileen, Winter, Alan D., Gillan, Victoria, Maitland, Kirsty, Emes, Richard D., Roberts, BBrett, McCormack, Gillian, Weir, William, Prostaio, Anna V., Holroyd, Nancy, Berriman, Matthew, Britton, Collette, and Devaney, Eileen
- Abstract
Background: Filarial nematodes are important pathogens in the tropics transmitted to humans via the bite of blood sucking arthropod vectors. The molecular mechanisms underpinning survival and differentiation of these parasites following transmission are poorly understood. microRNAs are small non-coding RNA molecules that regulate target mRNAs and we set out to investigate whether they play a role in the infection event. Results: microRNAs differentially expressed during the early post-infective stages of Brugia pahangi L3 were identified by microarray analysis. One of these, bpa-miR-5364, was selected for further study as it is upregulated ~12-fold at 24 hours post-infection, is specific to clade III nematodes, and is a novel member of the let-7 family, which are known to have key developmental functions in the free-living nematode Caenorhabditis elegans. Predicted mRNA targets of bpa-miR-5364 were identified using bioinformatics and comparative genomics approaches that relied on the conservation of miR-5364 binding sites in the orthologous mRNAs of other filarial nematodes. Finally, we confirmed the interaction between bpa-miR-5364 and three of its predicted targets using a dual luciferase assay. Conclusions: These data provide new insight into the molecular mechanisms underpinning the transmission of third stage larvae of filarial nematodes from vector to mammal. This study is the first to identify parasitic nematode mRNAs that are verified targets of specific microRNAs and demonstrates that post-transcriptional control of gene expression via stage-specific expression of microRNAs may be important in the success of filarial infection.
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36. Regulation of immune responses by the L3 of Brugia pahangi
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Gillan, Victoria Ann and Gillan, Victoria Ann
- Abstract
Lymphatic filarial worms are mosquito borne parasites which cause chronic disease in humans. Infection is characterized by proliferative suppression of T cells in the host and a skewing of the immune response, away from an IFN-gamma producing Th1 response, towards a Th2 or regulatory phenotype, with production of IL-4 and IL-10. In this study, a mouse model was used to investigate the role of the infective form of the parasite (the third stage larvae, L3) in regulating immune responses. BALB/c mice were infected by the subcutaneous route to mimic the natural transmission of the parasite, and immune responses generated by the L3 were analysed. Experiments carried out in the intact BALB/c mouse showed that infection with L3 results in increased IL-4, IL-10 and IL-5 with no IL-2 or IFN-gamma, a similar situation to that observed in infected humans. In order to investigate the key components in this skewing of the immune response, experiments were carried out using IL-4-/- mice. IL-4 was shown to have a role in down-regulating Th1 responses in wild type mice, as knock-out animals produced elevated levels of IL-2 and IFN-gamma. However these mice still had the capacity to produce IL-5, IL-13 and IL-10, suggesting that although IL-4 is an important Th2 cytokine, it may be dispensable in the initiation of such a response. In addition, reduced levels of proliferation of CD4+ and B220+ cells were observed in infected IL-4-/- mice. Despite elevated levels of IFN-gamma, this reduction in proliferation was not associated with increased production of NO, and neutralizing IFN-gamma itself did not restore proliferative responses. Addition of rIL-4 to cultures of splenocytes from these mice had a mild effect but did not result in a significant increase in proliferation. Treatment of splenocytes from intact mice with anti-IL-10 MAb in vitro resulted in increased levels of IL-2 and IFN-gamma, but no significant effect on Ag-specific proliferation was observed. However, when mice were
37. Characterisation of infection associated microRNA and protein cargo in extracellular vesicles of Theileria annulata infected leukocytes.
- Author
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Gillan V, Simpson DM, Kinnaird J, Maitland K, Shiels B, and Devaney E
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- Animals, Cattle, Cell Line, Extracellular Vesicles chemistry, Extracellular Vesicles metabolism, Leukocytes metabolism, Leukocytes parasitology, MicroRNAs analysis, Proteins analysis, Theileria annulata growth & development
- Abstract
The protozoan parasites Theileria annulata and Theileria parva are unique amongst intracellular eukaryotic pathogens as they induce a transformation-like phenotype in their bovine host cell. T. annulata causes tropical theileriosis, which is frequently fatal, with infected leukocytes becoming metastatic and forming foci in multiple organs resulting in destruction of the lymphoid system. Exosomes, a subset of extracellular vesicles (EV), are critical in metastatic progression in many cancers. Here, we characterised the cargo of EV from a control bovine lymphosarcoma cell line (BL20) and BL20 infected with T. annulata (TBL20) by comparative mass spectrometry and microRNA (miRNA) profiling (data available via ProteomeXchange, identifier PXD010713 and NCBI GEO, accession number GSE118456, respectively). Ingenuity pathway analysis that many infection-associated proteins essential to migration and extracellular matrix digestion were upregulated in EV from TBL20 cells compared with BL20 controls. An altered repertoire of host miRNA, many with known roles in tumour and/or infection biology, was also observed. Focusing on the tumour suppressor miRNA, bta-miR-181a and bta-miR-181b, we identified putative messenger RNA targets and confirmed the interaction of bta-miR181a with ICAM-1. We propose that EV and their miRNA cargo play an important role in the manipulation of the host cell phenotype and the pathobiology of Theileria infection., (© 2018 The Authors Cellular Microbiology Published by John Wiley & Sons Ltd.)
- Published
- 2019
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38. Characterization of HSP90 isoforms in transformed bovine leukocytes infected with Theileria annulata.
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Kinnaird JH, Singh M, Gillan V, Weir W, Calder ED, Hostettler I, Tatu U, Devaney E, and Shiels BR
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- Animals, Cattle, Cells, Cultured, HSP90 Heat-Shock Proteins analysis, Leukocytes parasitology, Organelles enzymology, Protein Isoforms analysis, Theileria annulata enzymology
- Abstract
HSP90 chaperones are essential regulators of cellular function, as they ensure the appropriate conformation of multiple key client proteins. Four HSP90 isoforms were identified in the protozoan parasite Theileria annulata. Partial characterization was undertaken for three and localization confirmed for cytoplasmic (TA12105), endoplasmic reticulum (TA06470), and apicoplast (TA10720) forms. ATPase activity and binding to the HSP90 inhibitor geldanamycin were demonstrated for recombinant TA12105, and all three native forms could be isolated to varying extents by binding to geldanamycin beads. Because it is essential, HSP90 is considered a potential therapeutic drug target. Resistance to the only specific Theileriacidal drug is increasing, and one challenge for design of drugs that target the parasite is to limit the effect on the host. An in vitro cell culture system that allows comparison between uninfected bovine cells and the T. annulata-infected counterpart was utilized to test the effects of geldanamycin and the derivative 17-AAG. T. annulata-infected cells had greater tolerance to geldanamycin than uninfected cells yet exhibited significantly more sensitivity to 17-AAG. These findings suggest that parasite HSP90 isoform(s) can alter the drug sensitivity of infected host cells and that members of the Theileria HSP90 family are potential targets worthy of further investigation., (©2016 The Authors. Cellular Microbiology published by John Wiley & Sons Ltd.)
- Published
- 2017
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39. A repurposing strategy for Hsp90 inhibitors demonstrates their potency against filarial nematodes.
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Gillan V, O'Neill K, Maitland K, Sverdrup FM, and Devaney E
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- Animals, Drug Repositioning, Enzyme Inhibitors chemistry, Female, Filaricides chemistry, Humans, Isoxazoles pharmacology, Male, Mice, Mice, Inbred BALB C, Resorcinols pharmacology, Brugia pahangi drug effects, Enzyme Inhibitors pharmacology, Filariasis parasitology, Filaricides pharmacology, HSP90 Heat-Shock Proteins antagonists & inhibitors
- Abstract
Novel drugs are required for the elimination of infections caused by filarial worms, as most commonly used drugs largely target the microfilariae or first stage larvae of these infections. Previous studies, conducted in vitro, have shown that inhibition of Hsp90 kills adult Brugia pahangi. As numerous small molecule inhibitors of Hsp90 have been developed for use in cancer chemotherapy, we tested the activity of several novel Hsp90 inhibitors in a fluorescence polarization assay and against microfilariae and adult worms of Brugia in vitro. The results from all three assays correlated reasonably well and one particular compound, NVP-AUY922, was shown to be particularly active, inhibiting Mf output from female worms at concentrations as low as 5.0 nanomolar after 6 days exposure to drug. NVP-AUY922 was also active on adult worms after a short 24 h exposure to drug. Based on these in vitro data, NVP-AUY922 was tested in vivo in a mouse model and was shown to significantly reduce the recovery of both adult worms and microfilariae. These studies provide proof of principle that the repurposing of currently available Hsp90 inhibitors may have potential for the development of novel agents with macrofilaricidal properties.
- Published
- 2014
- Full Text
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