Martin Sheldon PhD FRCVS

Professor Emeritus 

Biography

Martin Sheldon qualified as a veterinary surgeon in 1984 (BVSc, MRCVS), and was awarded two Diplomas (DBR, DCHP) whilst working in clinical practice in Wales. He moved to the Royal Veterinary College, London in 1998, becoming Professor of Veterinary Reproduction. He also completed a PhD thesis on postpartum uterine disease in 2002, supervised by Prof Hilary Dobson at the University of Liverpool. Prof Sheldon was awarded a BBSRC Research Development Fellowship in 2005, FRCVS for meritorious contributions to research in 2013, and the Schofield Prize in 2015. He was Professor of Reproductive Immunobiology at Swansea University Medical School between 2008 and 2024.

Research Interests

Resilience - Immunology - Infection - Reproduction 

Prof Sheldon discovered that ovarian function is perturbed in animals with uterine bacterial co-infections. He initially worked out how the main pathogenic bacteria cause co-infections that lead to inflammation and tissue damage in the endometrium, and how this infection and inflammation affects the ovary. Key discoveries were that the epithelial and stromal cells of the endometrium, and the granulosa cells of the ovary have roles in innate immunity. These cells express receptors, such as Toll-like Receptors (TLRs), which detect pathogen-associated molecular patterns to induce inflammatory responses, including the production of cytokines, chemokines and prostaglandins. Furthermore, pathogen-associated molecules impair oocyte health and perturb embryo development. These findings link bacterial infections to long-term impacts on fertility.

Prof Sheldon also explored the impact on tissues of pore-forming toxins, which are the most common virulence factor used by bacteria to damage host cells. He found that cells can be protected against  pore-forming toxins by manipulating the cholesterol biosynthesis and homeostasis pathways, using statins, LXR agonists, or oxysterols. Finding ways to protect cells against bacterial virulence factors is an alternative to using antimicrobials to kill bacteria, which helps in the fight against antimicrobial resistance.

Finally, Prof Sheldon worked on how the endocrine system and hormones affect host resilience. It is well-established that the female sex hormones and corticosteroids affect immunity, but the mechanisms are not clear. Progesterone helps establish infections in the uterus, but endometrial cell immune responses were not affected by the female sex hormones. However, corticosteroids and oxysterols stimulate the intrinsic protection of tissue cells against pathogens to improve host resilience. Oxysterols likely act as signaling molecules so that cells exposed to pathogens secrete oxysterols to enhance the resilience of nearby cells.

Selected publications

Ormsby TJR, Owens SE, Horlock AD, Davies D, Griffiths WJ, Wang Y, Cronin JG, Bromfield JJ, Sheldon IM. 2021 Oxysterols protect bovine endometrial cells against pore-forming toxins from pathogenic bacteria. The FASEB Journal 35:e21889.

Horlock AD, Piersanti RL, Ramirez-Hernandez R, Yu F, Ma Z, Jeong KC, Clift MJD, Block J, Santos JEP, Bromfield JJ, Sheldon IM. 2020 Uterine infection alters the transcriptome of the bovine reproductive tract three months later. Reproduction 160(1):93-107 

Pospiech M, Owens SE, Miller DJ, Austin-Muttitt K, Mullins JGL, Cronin JG, Allemann RK, Sheldon IM. 2021. Bisphosphonate inhibitors of squalene synthase protect cells against cholesterol-dependent cytolysins. The FASEB Journal  35(6), e21640. 

Sheldon IM, Cronin JG, Bromfield JJ. 2019 Tolerance and Innate Immunity Shape the Development of Postpartum Uterine Disease and the Impact of Endometritis in Dairy Cattle. Annual Review of Animal Biosciences, 7,  361-384 

Amos MR, Healey GD, Goldstone RJ, Mahan SM, Düvel A, Schuberth HJ, Sandra O, Zieger P, Dieuzy-Labaye I, Smith DGE, Sheldon IM 2014 Differential Endometrial Cell Sensitivity to a Cholesterol-Dependent Cytolysin Links Trueperella pyogenes to Uterine Disease in Cattle. Biology of Reproduction 90, 54, 1-13

Cronin JG, Turner ML, Goetze L, Bryant CE, Sheldon IM, 2012 Toll-Like Receptor 4 and MYD88-Dependent Signaling Mechanisms of the Innate Immune System are Essential for the Response to Lipopolysaccharide by Epithelial and Stromal Cells of the Bovine Endometrium. Biology of Reproduction 86: 51

Bromfield JJ, Sheldon IM, 2011 Lipopolysaccharide Initiates Inflammation in Bovine Granulosa Cells via the TLR4 Pathway and Perturbs Oocyte Meiotic Progression in Vitro. Endocrinology 152: 5029-5040

Herath S, Williams EJ, Lilly ST, Gilbert RO, Dobson H, Bryant CE, Sheldon IM, 2007 Ovarian follicular cells have innate immune capabilities that modulate their endocrine function.   Reproduction 134: 683-693

Herath S, Fischer DP, Werling D, Williams EJ, Lilly ST, Dobson H, Bryant CE, Sheldon IM, 2006 Expression and function of Toll-like receptor 4 in the endometrial cells of the uterus. Endocrinology 147:562-570

Sheldon IM, Noakes DE, Rycroft AN, Pfeiffer DU, Dobson H, 2002 Influence of uterine bacterial contamination after parturition on ovarian dominant follicle selection and follicle growth and function in cattle. Reproduction 123:837-845

See below for full list of publications

Funding

BBSRC, NIH (USA), NRN (Wales), the Royal Society, Wellcome Trust, OECD, industry, and the RCVS.

Science


Uterine disease impairs ovarian function and ooctye health

Uterine disease reduces ovarian follicle growth rates, the likelihood of ovulation, damages oocytes, and the proportion of oocytes that developed to morulae following in vitro fertilization. 

For more details see: 10.1093/biolre/ioaa069   10.1210/en.2011-1124  and   10.1530/rep.0.1230837   

Improving resilience against pathogenic bacteria

Resilient animals prevent the development of disease by avoiding, tolerating and resisting infection.

For more details see: 10.1016/j.theriogenology.2020.01.017 ).

Avoiding, tolerating and resisting pathogenic bacteria


Preventing postpartum uterine disease

For more details see: 

https://www.youtube.com/watch?v=DFN3kAv9KTU

Impact

Protecting tissues against damage caused by bacteria

Tissue damage is a common feature of bacterial diseases. Many species of pathogenic bacteria produce toxins that form holes in cell membranes, which can cause cell death. However, tissue cells vary in their ability to protect themselves against these toxins. Furthermore, hormones and drugs can increase the resilience of cell membranes to pore-forming toxins. 

Uterine infection and infertility in dairy cows

Bacterial infections of the uterus are a worldwide problem for dairy cows because they cause disease and infertility in more than 40% of animals. Infections disrupt the function of the uterus and impair the health of eggs in the ovary. Improving animal welfare depends on increasing the resilience of cows to infections, and by developing novel approaches for the treatment and prevention of disease.

Publications                                                                                  Google Scholar             Scopus  

Book chapters

Sheldon IM 2018 Chapter 23: The Metritis Complex in Cattle. Editors: David E. Noakes, Timothy J. Parkinson, Gary C.W. England, Veterinary Reproduction & Obstetrics 10th Edition, WB Saunders. ISBN 9780702072338, 408-433, DOI 10.1016/B978-0-7020-7233-8.00023-9.

Sheldon IM, Price JC, Turner ML, Bromfield JJ, Cronin JJ 2014 Uterine infection and immunity in cattle. In “Reproduction in Domestic Ruminants VIII”, pp 415-430. Editors: Juengel JJ, Miyamoto A, Price C, Reynolds LP, Smith MF, Webb R. Published by Context Products Ltd, Ashby de la Zouch, UK.

Sheldon IM, Barrett DC and Boyd H 2003 The postpartum period. In Bovine Medicine 2nd Edition. Editor: AH Andrews.  Blackwell Publishing Ltd, Oxford. pp 508-529 

Sheldon IM 2002 Reproductive challenges facing the cattle industry at the beginning of the 21st century. In Reproduction in Domestic Ruminants V. Cambridge, SRF. pp 1-13

Sheldon IM 2001 The caesarean operation and the surgical preparation of teaser males. Editors: David E. Noakes, Timothy J. Parkinson, Gary C.W. England: Arthur's Veterinary Reproduction and Obstetrics. London, WB Saunders. pp 341-365