Website The University of Birmingham
Project Details:
Bacterial lipopolysaccharide (LPS) and activation of Toll-like Receptor 4 (TLR4; aided by CD14 and MD-2) are important for reducing the risk of developing Type 1 diabetes in both mice and humans (1; 2). Part of this protection is believed to be through induction of an anti-inflammatory immune profile including IL-10. Furthermore, increases in the abundance of Bacteroidetes bacteria, which are dominant producers of LPS (3), can identify individuals at risk of, or living with, Type 1 diabetes, compared to individuals without Type 1 diabetes (4-10); however, LPS from these expanded Bacteroidetes bacteria are poor stimulators of TLR4 (3; 11). Additionally, our data indicate that LPS-sequestering proteins are altered in those with Type 1 diabetes, potentially further limiting the ability of LPS to activate TLR4 and induce anti-inflammatory IL-10 secretion by immune cells.
The student selected for this PhD project will aim to understand:
1. Whether LPS-sequestering proteins such as LBP, CD14 and anti-LPS antibodies reduce TLR4 signalling in immune cells in people with, or at risk of, Type 1 diabetes
2. How structurally different LPS molecules from different bacterial donors influence anti-LPS immune responses
3. Whether any of these anti-LPS immune markers could be novel biomarkers for identifying those at risk of developing Type 1 diabetes
This project will involve working with a multidisciplinary team of researchers across Birmingham and Bristol in the UK and Indiana and Western Michigan in the USA to obtain key samples (serum/plasma and peripheral blood mononuclear cells) for study. The student will be trained in and learn many different experimental methods, including ELISA, flow cytometry, in vitro cell culturing and bioinformatic analyses. Work in vivo, in mice that develop spontaneous diabetes, may also be performed depending on the student’s interest.
The student will join a growing World-leading Diabetes research team at the University of Birmingham comprising many PIs including Professor Parth Narendran, Professor Colin Dayan, Professor David Wraith, Dr Danijela Tatovic and Dr Pete Taylor among others.
Person Specification
Applicants should have a strong background in immunology, and ideally a background in type 1 diabetes/autoimmunity. They should have a commitment to research in studying the immune system and hold or realistically expect to obtain at least an Upper Second Class Honours Degree in a relevant subject.
How to apply
Informal enquiries and applications should be directed to Dr James Pearson – j.a.pearson@bham.ac.uk
To apply, please send:
• A detailed CV, including your nationality and country of birth;
• Names and addresses of two referees;
• A covering letter highlighting your research experience/capabilities;
• Copies of your degree certificates with transcripts;
• Evidence of your proficiency in the English language, if applicable.
Funding Notes
This project is funded through the University of Birmingham 125th Anniversary Fellowship Scheme and a Breakthrough T1D grant.
References
1. Vatanen T, Kostic AD, d’Hennezel E, Siljander H, Franzosa EA, Yassour M, Kolde R, Vlamakis H, Arthur TD, Hämäläinen AM, Peet A, Tillmann V, Uibo R, Mokurov S, Dorshakova N, Ilonen J, Virtanen SM, Szabo SJ, Porter JA, Lähdesmäki H, Huttenhower C, Gevers D, Cullen TW, Knip M, Xavier RJ, Group DS. Variation in Microbiome LPS Immunogenicity Contributes to Autoimmunity in Humans. Cell 2016;165:842-853
2. Gülden E, Ihira M, Ohashi A, Reinbeck AL, Freudenberg MA, Kolb H, Burkart V. Toll-like receptor 4 deficiency accelerates the development of insulin-deficient diabetes in non-obese diabetic mice. PLoS One 2013;8:e75385
3. d’Hennezel E, Abubucker S, Murphy LO, Cullen TW. Total Lipopolysaccharide from the Human Gut Microbiome Silences Toll-Like Receptor Signaling. mSystems 2017;2
4. Giongo A, Gano KA, Crabb DB, Mukherjee N, Novelo LL, Casella G, Drew JC, Ilonen J, Knip M, Hyöty H, Veijola R, Simell T, Simell O, Neu J, Wasserfall CH, Schatz D, Atkinson MA, Triplett EW. Toward defining the autoimmune microbiome for type 1 diabetes. ISME J 2011;5:82-91
5. de Goffau MC, Luopajärvi K, Knip M, Ilonen J, Ruohtula T, Härkönen T, Orivuori L, Hakala S, Welling GW, Harmsen HJ, Vaarala O. Fecal microbiota composition differs between children with β-cell autoimmunity and those without. Diabetes 2013;62:1238-1244
6. de Goffau MC, Fuentes S, van den Bogert B, Honkanen H, de Vos WM, Welling GW, Hyoty H, Harmsen HJ. Aberrant gut microbiota composition at the onset of type 1 diabetes in young children. Diabetologia 2014;57:1569-1577
7. Kostic AD, Gevers D, Siljander H, Vatanen T, Hyötyläinen T, Hämäläinen AM, Peet A, Tillmann V, Pöhö P, Mattila I, Lähdesmäki H, Franzosa EA, Vaarala O, de Goffau M, Harmsen H, Ilonen J, Virtanen SM, Clish CB, Orešič M, Huttenhower C, Knip M, Xavier RJ, Group DS. The dynamics of the human infant gut microbiome in development and in progression toward type 1 diabetes. Cell Host Microbe 2015;17:260-273
8. Alkanani AK, Hara N, Gottlieb PA, Ir D, Robertson CE, Wagner BD, Frank DN, Zipris D. Alterations in Intestinal Microbiota Correlate With Susceptibility to Type 1 Diabetes. Diabetes 2015;64:3510-3520
9. Stewart CJ, Ajami NJ, O’Brien JL, Hutchinson DS, Smith DP, Wong MC, Ross MC, Lloyd RE, Doddapaneni H, Metcalf GA, Muzny D, Gibbs RA, Vatanen T, Huttenhower C, Xavier RJ, Rewers M, Hagopian W, Toppari J, Ziegler AG, She JX, Akolkar B, Lernmark A, Hyoty H, Vehik K, Krischer JP, Petrosino JF. Temporal development of the gut microbiome in early childhood from the TEDDY study. Nature 2018;562:583-588
10. Vatanen T, Franzosa EA, Schwager R, Tripathi S, Arthur TD, Vehik K, Lernmark Å, Hagopian WA, Rewers MJ, She JX, Toppari J, Ziegler AG, Akolkar B, Krischer JP, Stewart CJ, Ajami NJ, Petrosino JF, Gevers D, Lähdesmäki H, Vlamakis H, Huttenhower C, Xavier RJ. The human gut microbiome in early-onset type 1 diabetes from the TEDDY study. Nature 2018;562:589-594
11. Yoshida N, Yamashita T, Kishino S, Watanabe H, Sasaki K, Sasaki D, Tabata T, Sugiyama Y, Kitamura N, Saito Y, Emoto T, Hayashi T, Takahashi T, Shinohara M, Osawa R, Kondo A, Yamada T, Ogawa J, Hirata KI. A possible beneficial effect of Bacteroides on faecal lipopolysaccharide activity and cardiovascular diseases. Sci Rep 2020;10:13009
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