This PhD opportunity is being offered as part of the LSTM and Lancaster University Doctoral Training Partnership. Find out more about the studentships and how to apply.
| Abstract | Parasitic nematodes cause significant medical and economic burden globally, yet there are still knowledge gaps in their basic biology hampering control and elimination. Screening published transcriptomes of parasitic nematodes revealed an abundant and diverse RNA virome of 91 viruses from 11 different viral orders within ~70% of nematodes that parasitize humans and economically important animals. Human-parasitic nematodes hosting these viruses cause significant public health issues, with >1.5 billion people currently infected with one or more such parasites. Parasitic nematodes have close associations with their host tissues, with individuals typically infected with multiple parasites simultaneously, as well as suffering life-long exposure to re-infection. This creates an environment which promotes direct exposure of the human host to these viruses. The full extent and diversity of the parasitic nematode RNA virome, how it impacts nematode biology, acts as drivers/modulators of disease pathogenesis and/or host immunity remain critical knowledge gaps. Extrapolation from the RNA viruses of protozoan parasites suggests potential roles in modulating disease pathology and progression as well as other fundamental biological processes. Both Leishmania virus (LRV1) and Trichomonas vaginalis virus (TVV) induce hyperinflammatory immunity, which drives disease pathogenesis and subverts host immunity to the parasites’ advantage. We showed that two viruses of filarial nematodes, Brugia malayi RNA virus 1 (BMRV1, Togaviridae) and Onchocerca volvulus RNA virus 1 (OVRV1, Rhabdoviridae) elicit antibody responses from the vertebrate host indicating exposure to and potential modulation of host immunity. To begin understanding the impact these viruses may have on the final host of the parasite, the PhD candidate will utilise lentiviral pseudotypes. These are modified, single-round Human Immunodeficiency Viruses (HIV)-based particles which are equipped with heterologous viral glycoproteins of interest, allowing us to study their binding and cellular entry-conferring properties . We have preliminary evidence for OVRV1 glycoprotein mediating entry into at least three different human cell lines. The candidate will look at broadly applying this approach using the glycoprotein of other viruses, e.g. viruses of the whipworm parasites Trichuris trichiura (infects humans) and T. muris (infects mice). T. trichiura is one of the most common human parasitic nematodes, infecting nearly half a billion people worldwide, whereas T. muris has an extensive history of use to study type 2 immune responses in laboratory animal models. Once successful infection using these modified lentiviruses has been validated, the candidate will then conduct additional experiments to further validate the relationship between virus and host. This includes, but is not limited to, competitive antibodies/peptides to inhibit glycoprotein-mediated entry, assessment of potential immune responses by the final host via transcriptomics, and/or validation of the target receptor used by the virus via CRISPR screening of the cell line. |
| Where does this project lie in the translational pathway? | T1 - Basic Research |
| Expected Outputs | Primary authorship on several impactful publications, as well as proof-of-concept data to support future grant applications for further research into an exciting and novel interdisciplinary field. This research has potentially significant translational impact, with the project potentially providing new data and perspectives on the pathology of parasitic nematode diseases, as well as host immunity. Specifically, Trichuris muris is a common laboratory model used to assess type 2 immune responses in mice, which are then translated into a human setting. |
| Training Opportunities | Training in skills for generating and utilising lentiviral pseudotypes in cell culture systems will be done by the Christine Goffinet lab, who has extensive experience in working with the human immunodeficiency lentivirus. The candidate can expect training in microscopy and parasitology identification techniques from the lab of Mark Taylor, as well as bioinformatics technique in transcriptomics for understanding immune responses. Additional training will also be provided for assessing the mechanism of action for infectivity from the lab of Alain Kohl. |
| Skills Required | A background in biomedical sciences with an interest in infectious disease, virology, and/or parasitology. Some experience in cell culture and molecular biology is desirable. |
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Key Publications associated with this project |
Quek, S., Hadermann, A., Wu, Y. et al. Diverse RNA viruses of parasitic nematodes can elicit antibody responses in vertebrate hosts. Nat Microbiol (2024). https://doi.org/10.1038/s41564-024-01796-6 (available on LSTM online archive) |
| de Carvalho, R.V.H., Lima-Junior, D.S., da Silva, M.V.G. et al. Leishmania RNA virus exacerbates Leishmaniasis by subverting innate immunity via TLR3-mediated NLRP3 inflammasome inhibition. Nat Commun 10, 5273 (2019). https://doi.org/10.1038/s41467-019-13356-2 | |
| Mhlekude, B. et al., Goffinet, C. Pharmacological inhibition of bromodomain and extra-terminal proteins induces an NRF-2-mediated antiviral state that is subverted by SARS-CoV-2 infection. PLoS Pathog. 19, e1011657 (2023). https://doi.org/10.1371/journal.ppat.1011657 | |
| Else, K.J., Keiser, J., Holland, C.V. et al. Whipworm and roundworm infections. Nat Rev Dis Primers 6, 44 (2020). https://doi.org/10.1038/s41572-020-0171-3 | |
| Hadermann, A., Amaral, L.J., Cutsem, G.V., et al. Onchocerciasis-associated epilepsy: an update and future perspectives. Trends Parasitol. 39, 2 (2023). https://doi.org/10.1016/j.pt.2022.11.010 |