Understanding Host Epigenetic changes to Salmonella Typhi Exposure and Infection in the context of a Human Challenge Model
Lead Research Organisation:
University of Oxford
Department Name: Paediatrics
Abstract
Enteric fever caused by Salmonella enterica serovars Typhi and Paratyphi A is an important cause of morbidity and mortality. Around 21 million people per year develop enteric fever of which approximately 222,000 die, with children being most at risk. The majority of cases arise in South-Central and Southeast Asia. There are several key challenges in preventing and managing typhoid infection including: difficulties in diagnosing enteric fever as current tests have poor sensitivity; short term vaccine efficacy, with no licensed vaccine for children under two years old; and the emergence of antibiotic resistant strains. Novel biomarkers of infection, more efficacious vaccines and novel anti-typhoid therapies are therefore needed; achieving these goals requires a better understanding of immune response to typhoid and in particular the role of innate and adaptive cellular immunity.
Enteric fever challenge studies, in which adults are challenged with a dose of typhoid bacteria with an attack rate of 65% in non-immune participants are currently being employed in Oxford to study immunity to these Salmonellae. Preliminary data show that infection, and vaccination alters gene expression in leukocytes and that these changes are associated with both immune responses and the inflammatory response during disease. How and why this occurs is governed by epigenetic mechanisms including DNA methylation and miR expression. MicroRNAs are a species of short non-coding RNA that post transcriptionally regulate 60% of genes. They are important mediators of host response to infection. MiRs are implicated in immune response e.g. miR-155 promotes an antimicrobial response by suppressing SOCS1 (suppression of cytokine signalling 1)to promote leukocyte secretion of pro-inflammatory cytokines4. MicroRNAs regulate differentiation and activation of B-cells, T-cells, monocytes and dendritic cells and therefore may govern host susceptibility to typhoid5-7.
Typhoid challenge studies present the opportunity to delineate immune response to a bacterial pathogen, at an epigenetic level, in a uniquely controlled environment. This study will use small RNA sequencing techniques and methylation chips to characterise microRNA and gene methylation changes after typhoid exposure and during typhoid infection in the PBMCs of participants of an enteric fever challenge study using stored samples. Epigenetic and pre-derived transcriptomic data will be integrated to provide an unprecedented level of detail in gene expression during exposure and infection. The functional significance of DNA methylation patterns and microRNAs will be determined using in-vitro studies. Data from this project could identify novel microRNA biomarkers of typhoid or bacterial infection, and may provide biological insights into the proteins and pathways which promote or prevent typhoid infection which could be exploited to facilitate the design of novel typhoid vaccines or anti-typhoid therapeutics.
Enteric fever challenge studies, in which adults are challenged with a dose of typhoid bacteria with an attack rate of 65% in non-immune participants are currently being employed in Oxford to study immunity to these Salmonellae. Preliminary data show that infection, and vaccination alters gene expression in leukocytes and that these changes are associated with both immune responses and the inflammatory response during disease. How and why this occurs is governed by epigenetic mechanisms including DNA methylation and miR expression. MicroRNAs are a species of short non-coding RNA that post transcriptionally regulate 60% of genes. They are important mediators of host response to infection. MiRs are implicated in immune response e.g. miR-155 promotes an antimicrobial response by suppressing SOCS1 (suppression of cytokine signalling 1)to promote leukocyte secretion of pro-inflammatory cytokines4. MicroRNAs regulate differentiation and activation of B-cells, T-cells, monocytes and dendritic cells and therefore may govern host susceptibility to typhoid5-7.
Typhoid challenge studies present the opportunity to delineate immune response to a bacterial pathogen, at an epigenetic level, in a uniquely controlled environment. This study will use small RNA sequencing techniques and methylation chips to characterise microRNA and gene methylation changes after typhoid exposure and during typhoid infection in the PBMCs of participants of an enteric fever challenge study using stored samples. Epigenetic and pre-derived transcriptomic data will be integrated to provide an unprecedented level of detail in gene expression during exposure and infection. The functional significance of DNA methylation patterns and microRNAs will be determined using in-vitro studies. Data from this project could identify novel microRNA biomarkers of typhoid or bacterial infection, and may provide biological insights into the proteins and pathways which promote or prevent typhoid infection which could be exploited to facilitate the design of novel typhoid vaccines or anti-typhoid therapeutics.
Publications
Cross D
(2019)
Epigenetics in Sepsis: Understanding Its Role in Endothelial Dysfunction, Immunosuppression, and Potential Therapeutics.
in Frontiers in immunology
Drury RE
(2021)
Symptom study app provides real-world data on COVID-19 vaccines.
in The Lancet. Infectious diseases
Drury RE
(2017)
The Clinical Application of MicroRNAs in Infectious Disease.
in Frontiers in immunology
O'Connor D
(2020)
Gene expression profiling reveals insights into infant immunological and febrile responses to group B meningococcal vaccine.
in Molecular systems biology
Studentship Projects
Project Reference | Relationship | Related To | Start | End | Student Name |
---|---|---|---|---|---|
MR/N013468/1 | 30/09/2016 | 29/09/2025 | |||
1960082 | Studentship | MR/N013468/1 | 30/09/2017 | 30/10/2021 | Ruth Drury |
Description | ESPID Annual Meeting Travel Award |
Amount | € 250 (EUR) |
Organisation | European Society for Paediatric Infectious Diseases (ESPID) |
Sector | Charity/Non Profit |
Country | Netherlands |
Start | 04/2018 |
End | 05/2018 |
Description | MRC Supplementary Funding Award: High-cost training in recognised areas of strategic need |
Amount | £10,000 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 05/2019 |
End | 08/2022 |
Title | MicroRNA microarray on infant plasma pre and post H1N1 vaccination |
Description | MicroRNA microarray on infant plasma pre and post H1N1 vaccination. Deposited on GEO: GSE134227 |
Type Of Material | Database/Collection of data |
Year Produced | 2019 |
Provided To Others? | Yes |
Impact | The study publication based on this data has been cited by others. It has also provided a useful reference for the importance of technical validation of miRNA array data. |
Description | Collaboration with proteomics research group at Target Discovery Institute at the University of Oxford |
Organisation | University of Oxford |
Department | Target Discovery Institute (TDI) |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | I provided samples from a clinical study to my collaborators so that mass spectroscopy for proteins could be done. I analysed the data the subsequent data that was produced |
Collaborator Contribution | My collaborators performed mass spectroscopy for proteins |
Impact | The dataset produced through this collaboration is the first mass spectroscopy data (according to literature) on vaccine-induced changes in the plasma proteome. The results have led to a follow up study looking at vaccine-induced changes in the plasma proteome in another cohort. Publication is expected in due course. |
Start Year | 2018 |
Description | Education session on clinical trials for 6th Formers |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | I led sessions on clinical trial design with local and international students visiting our department on two occasions. The centrepiece of the session was a hands-on activity designed to demonstrate the rationale of the randomised controlled blinded clinical trials. We had the students participate in a purposefully biased and flawed experiment involving the use of tomato and lime juice to reduce the experience of pain (they had to put their hands in cold iced water for up to 30 seconds), and as we went through the results we had them identify the issues with the study and come up solutions - i.e. they came up with the concepts relating to randomised controlled blinded clinical trials. The students were very engaged with the activity and we received good feedback. The activity was so successful that it was rolled out to engagement activities led by others in the group. |
Year(s) Of Engagement Activity | 2017 |
Description | Presentation at ESPID Annual General Meeting |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other audiences |
Results and Impact | Presentation of research project at International Conference. Several people asked me about the research afterwards and how it relates to their work. |
Year(s) Of Engagement Activity | 2018,2019,2021 |
Description | Provided an invited interview to a science journalist about the potentials of miRNA attenuated viral vaccines |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other audiences |
Results and Impact | Interviewed by a science journalist about the potentials of miRNA attenuated viral vaccines. Article published as a news feature in Nature Medicine. |
Year(s) Of Engagement Activity | 2018 |
URL | https://www.nature.com/articles/nm0318-248 |
Description | UNIQ+ Digital event: Presentation with Q&A for undergraduates considering post grad opportunities |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Undergraduate students |
Results and Impact | I gave a talk on my career so far and my experience of being part of the COVID-19 vaccine trials. I also fielded questions about how to overcome some of the disappointment and setbacks that people inevitably face as part of an academic career and how to build resilience. The audience appeared very engaged, and ask questions afterwards |
Year(s) Of Engagement Activity | 2021 |