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Supervisors:
Judith Breuer and Sofia Morfopoulou and Cristina Venturini
Project Description:
Background: High throughput sequencing (HTS) of all the nucleic acids in a clinical specimen in an untargeted manner has expanded our understanding of human illnesses through the study of pathogens1,2 and the associated study of host response to an infection1,3,4.
Aims: This PhD project aims to investigate the presence and transcriptional activity of pathogens and host gene expression in human diseases using untargeted metagenomic and metatranscriptomic HTS methods. Encephalitis, hepatitis and pneumonia in paediatric patients will be used as exemplars, but the methods developed as part of this project are expected to apply to a range of illnesses.
Methods: Metatranscriptomics from clinical specimens sequenced at the GOSH metagenomics pathogen detection service5, as well as publicly available RNA-sequencing datasets from the brain and liver, will be analysed to help identify signatures that differentiate between infectious and non-infectious manifestations of hepatitis and encephalitis. Data from GOSH have been sequenced, and ethics are in place (n= ~30 samples from paediatric cases of encephalitis, n= ~8 samples from paediatric cases of hepatitis, n= ~30 samples from paediatric cases of pneumonia). If relevant, new cases will be included through the GOSH metagenomics pathogen detection service or other relevant sources. The validation and performance of immune gene modules, groups of correlated expressed genes, for host profiling, will also be assessed, in tandem with interrogating the whole transcriptome from publicly available bulk and single-cell RNA sequencing data.
Timeline: In the first year, the student will focus on developing bioinformatics methods to analyse HTS data from clinical metagenomics and to detect novel pathogens. In the second year, the student will also work on creating host transcriptomic signatures from metatranscriptomics data using GOSH and publicly available samples. Then, in the final year, the student will assess the potential of these signatures for broader application in characterising diseases.
References:
1. Morfopoulou, S. et al. Genomic investigations of unexplained acute hepatitis in children. Nature 617, 564–573 (2023).
2. Penner, J. et al. Translating metagenomics into clinical practice of complex paediatric neurological presentations. 2023.06.02.23290816 Preprint at https://doi.org/10.1101/2023.06.02.23290816 (2023).
3. Kalantar, K. L. et al. Integrated host-microbe plasma metagenomics for sepsis diagnosis in a prospective cohort of critically ill adults. Nat Microbiol 7, 1805–1816 (2022).
4. Habgood-Coote, D. et al. Diagnosis of childhood febrile illness using a multi-class blood RNA molecular signature. Med 4, 635-654.e5 (2023).
5. Metagenomics Pathogen Detection. GOSH Hospital site https://www.gosh.nhs.uk/wards-and-departments/departments/laboratory-med....
Contact Information:
Sofia Morfopoulou ; Cristina Venturini