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The respiratory metagenome during exacerbations of asthma


Project Description

Asthma is an international pandemic, with 10% or more of the global population having experience asthma symptoms some time in life. Despite major advances in understanding asthma pathophysiology, hospitalisations and deaths remain at unacceptable levels. Furthermore, a large proportion of patients are not able to control their disease, with 5%-10% suffering from severe asthma, a debilitating and life-threatening condition. Most of the asthma morbidity and mortality is associated with acute attacks or exacerbations. There is clearly a profound unmet need to reduce the enormous disease burden of asthma and its comorbidities.
A key characteristic of asthma that remains relatively unexplored is susceptibility to infection. Acute asthma exacerbations are triggered, in the large majority of cases, by viral and possibly bacterial respiratory infections. Respiratory infections are also strongly associated with asthma initiation as well as airway remodelling and asthma persistence. The immune-microbial interaction (pathobiome) is a major driving source that can fix a particular microbiological niche in any tissue, including the respiratory. This niche in terms of modern research techniques can be studied with the use of metagenomics, i.e. the use of next generation sequencing to identify all RNA and DNA species found in a specific tissue site.
We hypothesise that during an acute upper respiratory infection, the microbial community of the airway is severely disrupted. The successful removal of the culprit agent and the reconstruction of a balanced microbial ecology, in parallel to the development or not of an acute exacerbation, depends upon the resilience of the existing microbiome – and particularly the virome – and is disturbed in patients with asthma. This PhD project will focus on the characterisation of the respiratory metagenome in relation to upper respiratory infections and exacerbations of asthma.

Training/techniques to be provided:
This is a wide and ambitious project, involving molecular biology techniques such as DNA and RNA isolation, DNA library preparation, whole genome amplification, next generation sequencing (Illumina), quantitative RT-PCR and gene expression assays. A variety of bioinformatics analysis will include raw read evaluation, annotation, binning and de novo assembly into contigs, use of ecological and genetic indexes such as alpha/beta diversities, phylogenetics and metagenome signatures. Statistical analysis will include principal coordinate analysis, principal component analysis, isomaping, multiple regression modelling and correlation statistics. Topographical analysis will also be used to construct and analyse microbial interactions with clinical scores. Furthermore, culture systems including cell isolation, air-liquid interphase models, co-culture models, diverse exposures and outcomes such as specific protein (ELISA, western blots, Luminex) or gene (PCR etc) quantification, and cellular functional assays.

Entry Requirements:
Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) and/or Master’s degree in a related area / subject. Candidates with experience in microbiology/cell biology or with an interest in bioinformatics are encouraged to apply.

For international students we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences. For more information please visit http://www.internationalphd.manchester.ac.uk

Funding Notes

Applications are invited from self-funded students. This project has a Band 3 fee. Details of our different fee bands can be found on our website (View Website). For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (View Website).

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

Spyridon Megremis, Katarzyna Niespodziana, Clarissa Cabauatan, Paraskevi Xepapadaki, Marek L Kowalski, Tuomas Jartti, Claus Bachert, Susetta Finotto, Peter West, Sofia Stamataki, Anna Lewandowska-Polak, Heikki Lukkarinen, Nan Zhang, Theodor Zimmermann, Frank Stolz, Angela Neubauer, Mübeccel Akdis, Evangelos Andreakos, Rudolf Valenta, Nikolaos G Papadopoulos (2018) Rhinovirus Species–Specific Antibodies Differentially Reflect Clinical Outcomes in Health and Asthma. Am J Respir Crit Care Med 198(1490-9).

Papadopoulos NG, Megremis S, Kitsioulis NA, Vangelatou O, West P, Xepapadaki P. (2017) Promising approaches for the treatment and prevention of viral respiratory illnesses. J Allergy Clin Immunol 140(4):921-932

Miller EK, Avila PC, Khan YW, Word CR, Pelz BJ, Papadopoulos NG, Peebles RS Jr, Heymann PW; Microbes, Allergy, and Asthma Committee. (2014) Wheezing exacerbations in early childhood: evaluation, treatment, and recent advances relevant to the genesis of asthma. J Allergy Clin Immunol Pract 2(5):537-43

Rose R, Constantinides B, Tapinos A, Robertson DL, Prosperi M. (2016) Challenges in the analysis of viral metagenomes. Virus Evolution 2(2).

Avraam Tapinos, Bede Constantinides, My VT Phan, Samaneh Kouchaki, Matthew Cotten, David L Robertson (2019) The Utility of Data Transformation for Alignment, De Novo Assembly and Classification of Short Read Virus Sequences. Viruses, 11(394).

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