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MRC DiMeN Doctoral Training Partnership: How does mosquito bite inflammation make virus infection worse?


Project Description

The climate crisis is making mosquito-borne virus infections an increasing threat to human health. These viruses, such as those that cause Zika and dengue, are infecting more people and spreading to new countries as the climate warms and globalisation helps mosquitoes spread.

These viruses are transmitted to people when biting mosquitoes spit virus into the skin. We have shown that inflammation caused by the mosquito bites helps these viruses replicate and spread around the body. We now have important new data that suggests patients with skin inflammatory disorders (psoriasis and eczema) may have different susceptibilities to these infections, and that this may relate to how immune defences are activated in the skin.

Psoriasis and eczema are debilitating skin conditions that affect approximately 3% of the global population. Skin from these patients exhibit abnormal expression of cytokines and leukocyte positioning. Patients typically require lifelong treatment with potent immune-modulating drugs (e.g. cytokine-neutralising antibodies).

Eczematous skin appears to be more susceptible to arbovirus infection, whilst psoriatic skin is less susceptible to infection. It is not clear why this is the case. Infection of the skin by these viruses represents an essential stage of virus life cycle; robust replication at this site is a pre-requisite for development of clinical disease. Aberrant positioning of the leukocytes in the skin of psoriasis/eczema patients and their ability to differentially secrete cytokines may account for differences in disease predisposition.

Objectives
To determine in eczematous/psoriatic skin how;
1. infection with arbovirus differs (e.g. magnitude, kinetics, and cellular tropism of virus)
2. leukocyte composition and positioning within the skin and their ability to activate anti-viral immune responses differs
In doing so, this new interdisciplinary project will uniquely combine aspects of dermatology, virology and immunology. It has potential to inform individualised patient care strategies for those at risk of infection; or if infected, help stratify clinical outcome.
We also expect that the emerging knowledge from this work, on the role of skin immune responses following arbovirus infection (eczema, psoriasis and healthy skin as exemplars), will open a unique opportunity to develop protective strategies that inhibit arbovirus infection in general. i.e. these studies will help us understand what types of inflammatory responses are key for fighting virus infection.

Experimental approach
1. We will compare ex vivo infection of human skin explants from healthy, psoriasis, eczema and treated patients. We will use Zika virus, an important and representative arbovirus, for which fluorescence expressing strains exist.
2. Inflammatory responses of skin cells will be characterised by transcriptome profiling of FACS isolated cells and validated by qPCR/immunohistochemistry.
3. In vivo experiments that target the most promising immune pathways will be performed using our established model

This project will provide training in key strategic priority areas that the wider academic community and biotech companies value, including; interdisciplinary approaches, quantitative skills (e.g. bioinformatics) and whole organism physiology (e.g. in vivo skills).

This project will be based in the Virus Host Interactions Team (VHIT) lead by Clive McKimmie. Please do check out our website and twitter feed for more info.
Any queries? Don’t hesitate to get in touch!

https://www.virus-host-interactions.org
https://twitter.com/VHIT_Mckimmie

Benefits of being in the DiMeN DTP:
This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.
We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.

Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards
Further information on the programme can be found on our website:
http://www.dimen.org.uk/

Funding Notes

Studentships are fully funded by the Medical Research Council (MRC) for 3.5yrs
Includes:
Stipend at national UKRI standard rate
Tuition fees
Research training and support grant (RTSG)
Travel allowance
Studentships commence: 1st October 2020.

To qualify, you must be a UK or EU citizen who has been resident in the UK/EU for 3 years prior to commencement. Applicants must have obtained, or be about to obtain, at least a 2.1 honours degree (or equivalent) in a relevant subject. All applications are scored blindly based on merit. Please read additional guidance here: View Website

Good luck!

References

Host Inflammatory Response to Mosquito Bites Enhances the Severity of Arbovirus Infection (2016) Pingen M, Bryden SR, Pondeville E, Schnettler E, Kohl A, Merits A, Fazakerley JK, Graham GJ, McKimmie CS. Immunity. 44, 1455–1469. This paper has the 2nd highest Altmetric score for an Immunity paper https://www.altmetric.com/details/8951929#score

Mosquito Biting Modulates Skin Response to Virus Infection (2017) Marieke Pingen, Michael Schmid, Eva Harris, and Clive S McKimmie. Trends in Parasitology, Aug;33(8):645-657.

Pan-viral protection against arboviruses by targeting inoculation site-based skin macrophages (2019) Steven R Bryden, Marieke Pingen, Daniella A Lefteri, Janne Miltenburg, , Leen Delang, Sofie Jacobs, Rana Abdelnabi, Johan Neyts, Jack Major, Henna Khalid, Marietta Muller, Andrew Tuplin, Andres Merits, Margus Varjak, Emilie Pondeville, Julia Edgar, Gerard J Graham, Kave Shams, Clive S McKimmie BioRxiv https://www.biorxiv.org/content/10.1101/566885v1

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