I. Martin Sheldon

I. Martin Sheldon
Swansea University | SWAN · Swansea University Medical School

BVSc DBR DCHP PhD FRCVS

About

183
Publications
115,489
Reads
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Introduction
Reproductive Immunobiology: I study mechanisms of interactions between hosts and pathogens. I am interested in how bacteria cause disease. On the other hand, I also aim to understand how animals and humans defend themselves against infections and prevent disease by avoiding, tolerating and resisting pathogenic bacteria. My first research question is about how bacteria cause inflammation and tissue damage in the uterus, and how this affects the ovary and oocyte. Key discoveries were that endometrial cells in the uterus, and granulosa cells in the ovary have roles in innate immunity. My second research question is how do cells protect themselves against pore-forming toxins? We study the cellular responses to pore-forming toxins and the mechanisms of cytoprotection against these toxins.
Additional affiliations
July 2008 - present
Swansea University
Position
  • Professor (Full)
December 1998 - July 2008
Royal Veterinary College
Position
  • Professor (Full)
July 1984 - November 1998
Ark Veterinary Group
Position
  • Medical Professional
Education
March 1998 - February 2002
University of Liverpool
Field of study
  • Veterinary Science
June 1993 - July 1995
Royal College of Veterinary Surgeons
Field of study
  • Cattle Health
October 1979 - July 1984
University of Liverpool
Field of study
  • Veterinary Science

Publications

Publications (183)
Preprint
Full-text available
Presenting information in papers allows readers to see the evidence for the research claims. The amount of information presented to readers is increasing in high impact factor scientific journals. The aim of the present study was to determine whether there was a similar expansion in the amount of information presented to readers in subject-specific...
Article
Full-text available
Pregnancy induces changes in the transcriptome of the bovine endometrium from 15 days after insemination. However, pregnancy is less likely to occur if cows had a postpartum bacterial infection of the uterus, even after the resolution of disease. We hypothesized that uterine bacterial infection alters the endometrial transcriptomic signature of pre...
Article
Full-text available
Many species of bacteria produce toxins such as cholesterol-dependent cytolysins that form pores in cell membranes. Membrane pores facilitate infection by releasing nutrients, delivering virulence factors, and causing lytic cell damage - cytolysis. Oxysterols are oxidized forms of cholesterol that regulate cellular cholesterol and alter immune resp...
Article
Full-text available
Many species of pathogenic bacteria secrete toxins that form pores in mammalian cell membranes. These membrane pores enable the delivery of virulence factors into cells, result in the leakage of molecules that bacteria can use as nutrients, and facilitate pathogen invasion. Inflammatory responses to bacteria are regulated by the side‐chain‐hydroxyc...
Article
Full-text available
Milk and dairy products provide highly sustainable concentrations of essential amino acids and other required nutrients for humans; however, amount of milk currently produced per dairy cow globally is inadequate to meet future needs. Higher performing dairy cows and herds produce more milk with less environmental impact per kg than lower performing...
Article
Full-text available
Certain species of pathogenic bacteria damage tissues by secreting cholesterol‐dependent cytolysins, which form pores in the plasma membranes of animal cells. However, reducing cholesterol protects cells against these cytolysins. As the first committed step of cholesterol biosynthesis is catalyzed by squalene synthase, we explored whether inhibitin...
Article
Bovine granulosa cells are often exposed to energy stress, due to the energy demands of lactation, and exposed to lipopolysaccharide from postpartum bacterial infections. Granulosa cells mount innate immune responses to lipopolysaccharide, including the phosphorylation of mitogen-activated protein kinases and production of pro-inflammatory interleu...
Article
Bovine endometrium consists of epithelial and stromal cells that respond to conceptus interferon tau (IFNT), the maternal recognition of pregnancy (MRP) signal, by increasing expression of IFN-stimulated genes (ISGs). Endometrial epithelial and stromal cell specific ISGs are largely unknown but hypothesized to have essential functions during pregna...
Article
Full-text available
Postpartum uterine infection reduces fertility in dairy cattle; however, the mechanisms of uterine infection‐mediated infertility are unknown. Paradoxically, infection‐induced infertility persists after the resolution of disease. Oocytes are a finite resource, which are present at various stages of development during uterine infection. It is likely...
Article
Uterine infection is associated with infertility in women and dairy cows, even after the resolution of infection. However, the mechanisms causing this persistent infertility are unclear. Here, we hypothesized that induced endometritis in non-lactating dairy cows would reduce the developmental competence of oocytes. Non-lactating Holstein cows recei...
Article
Infection of the postpartum uterus with pathogenic bacteria is associated with infertility months later in dairy cattle. However, it is unclear whether these bacterial infections lead to long-term changes in the reproductive tract that might help explain this infertility. Here we tested the hypothesis that infusion of pathogenic bacteria into the u...
Article
Full-text available
Pathogenic bacteria often damage tissues by secreting toxins that form pores in cell membranes, and the most common pore-forming toxins are cholesterol-dependent cytolysins. During bacterial infections, glutamine becomes a conditionally essential amino acid, and glutamine is an important nutrient for immune cells. However, the role of glutamine in...
Article
Full-text available
Forkhead Box L2 (FOXL2) is a member of the FOXL class of transcription factors, which are essential for ovarian differentiation and function. In the endometrium, FOXL2 is also thought to be important in cattle; however, it is not clear how its expression is regulated. The maternal recognition of pregnancy signal in cattle, interferon-Tau, does not...
Article
Up to forty percent of dairy cows develop metritis or endometritis when pathogenic bacteria infect the uterus after parturition. However, resilient cows remain healthy even when exposed to the same pathogens. Here, we provide a perspective on the mechanisms that dairy cows use to prevent postpartum uterine disease. We suggest that resilient cows pr...
Article
Communication between the oocyte and cumulus facilitates oocyte growth, cell cycle regulation, and metabolism. This communication is mediated by direct contact between oocytes and cumulus cells, and soluble secreted molecules. Secreted molecules involved in this process are known inflammatory mediators. Lipopolysaccharide (LPS) is detected in folli...
Preprint
Full-text available
Up to forty percent of dairy cows can develop metritis or endometritis when bacteria infect the uterus after parturition. However, it is unclear why other cows exposed to similar pathogens do not develop uterine disease. We suggest that resilient dairy cows prevent the development of uterine disease using the three complimentary defensive strategie...
Article
Full-text available
Cattle with subclinical endometritis (SCE) are sub-fertile and diagnosing subclinical uterine disease remains a challenge. The hypothesis for this study was that endometrial inflammation is reflected in mRNA expression patterns of peripheral blood leucocytes. Transcriptome profiles were evaluated in healthy cows and in cows with SCE using circulati...
Preprint
Full-text available
Pathogenic bacteria often damage tissues by secreting toxins that form pores in cell membranes, and the most common pore-forming toxins are cholesterol-dependent cytolysins. During bacterial infections, glutamine becomes a conditionally essential amino acid, and glutamine is an important nutrient for immune cells. However, the role of glutamine in...
Article
In mammals, tight regulation of maternal endometrial function is critical for pregnancy success. In bovine species, endometrial expression of members of the scavenger receptor class A (SR-A) has been listed in high-throughput analyses, but very little is known about the involvement of these immune factors during implantation in mammals. To provide...
Article
Full-text available
Microbes commonly infect the female genital tract of cattle, causing uterine disease, abortion, and infertility. In particular, postpartum uterine disease develops in about 40% of dairy cows following infections with Gram-negative Escherichia coli and Gram-positive bacteria, such as Trueperella pyogenes. These infections damage tissues and cause in...
Article
Metritis is associated with reduced fertility in dairy cows, but the mechanisms are unclear because the disease resolves several weeks before insemination. One hypothesis is that metritis causes persistent changes in granulosa cells during follicle development, which might be evident in the transcriptome of granulosa cells from dominant follicles w...
Article
Bacterial infection of the uterus causes clinical endometritis in 15 to 20% of postpartum dairy cows and reduces fertility, even after the resolution of disease. However, it is difficult to disentangle the mechanisms linking reduced fertility with endometritis because cows have multiple confounding postpartum conditions. The aim of the present expe...
Article
Full-text available
Infections of the female reproductive tract are a major cause of morbidity and mortality in humans, requiring significant investment to sustain treatment and representing a major challenge to health. The increasing prevalence of bacterial resistance, and an almost complete absence of new antibiotic therapies for the past five decades, mean there is...
Article
Bacteria are ubiquitous in the uterus of cattle after parturition, but 50 years ago, cows tolerated these bacteria and few animals developed uterine disease. Now, up to 40% of dairy cattle develop postpartum uterine disease. Uterine disease causes infertility by compromising not only the function of the endometrium but also the ovary. Animals defen...
Chapter
This book chapter describes the causes, consequences, and treatment of postpartum uterine diseases, such as metritis and endometritis. Please REQUEST A COPY from me if you want to read more.
Article
Full-text available
Preventing postpartum uterine disease depends on the ability of endometrial cells to tolerate the presence of the bacteria that invade the uterus after parturition. Postpartum uterine disease and endometrial pathology in cattle is most associated with the pathogen Trueperella pyogenes. Trueperella pyogenes secretes a cholesterol-dependent cytolysin...
Article
Full-text available
The worldwide population in 2067 will reach 10.4 billion with 81% residing in Africa or Asia. Arable land available for food production will decrease to 0.15 ha per person. Temperature will increase in tropical and temperate zones, especially in the Northern Hemisphere, and this will push growing seasons and dairy farming away from arid areas and i...
Article
Full-text available
Intensive selection for milk production has led to reduced reproductive efficiency in high-producing dairy cattle. The impact of intensive milk production on oocyte quality as well as early embryo development has been established but few analyses have addressed this question at the initiation of implantation, a critical milestone ensuring a success...
Data
Primer information used for quantitative real time PCR analysis of bovine candidate genes. All primers were used at a concentration of 300 nM in a final reaction volume of 15 μl. (XLSX)
Article
Full-text available
Animal health depends on the ability of immune cells to kill invading pathogens, and on the resilience of tissues to tolerate the presence of pathogens. Trueperella pyogenes causes tissue pathology in many mammals by secreting a cholesterol-dependent cytolysin, pyolysin (PLO), which targets stromal cells. Cellular cholesterol is derived from squale...
Data
Supplementary Information Inhibiting mevalonate pathway enzymes increases stromal cell resilience to a cholesterol-dependent cytolysin Sholeem Griffin, Giulio Preta, I Martin Sheldon
Article
Full-text available
Bacterial infections of the uterus after parturition are ubiquitous in dairy cattle and often cause uterine disease, such as metritis or endometritis. However, the metabolic stress associated with milk production increases the risk of developing disease. Resolution of bacterial infections requires rapid and robust innate immune responses, which dep...
Article
Full-text available
Bovine herpesvirus-4 (BoHV-4) and bovine viral diarrhea virus (BVDV) infect the uterus of cattle, often resulting in reduced fertility, or abortion of the fetus, respectively. Here, exposure of primary bovine endometrial cells to BoHV-4 or BVDV modulated the production of inflammatory mediators. Viral pathogen-associated molecular patterns (PAMPs)...
Article
Full-text available
Bacteria infect the endometrium lining the uterus of cattle after parturition, and clearance of these microbes depends on a robust innate immune response to bacterial molecules, such as the endotoxin lipopolysaccharide (LPS). Endometrial inflammation is characterized by secretion of the cytokines IL-1β and IL-6 and the chemokine IL-8. However, anim...
Article
Full-text available
After parturition, uterine involution, regeneration of the endometrium, return of ovarian cyclic activity, and the control of pathogenic bacteria in the uterus is required before cows are likely to conceive again. However, pathogenic bacteria often cause uterine disease in modern dairy cattle, leading to decreased productivity and reduced fertility...
Article
Full-text available
Tissue homeostasis in the female genital tract is challenged by infection, damage, and even physiological events during reproductive cycles. We propose that the evolutionarily ancient system of innate immunity is sufficient to sense and respond to danger in the non-pregnant female genital tract. Innate immunity produces a rapidly inducible, non-spe...
Conference Paper
Full-text available
Cholesterol-dependent cytolysins (CDC) are commonbacterial virulence factors that bind cholesterol to form pores in the plasma membrane of mammalian cells, leading to osmotic cell death. Pyolysin is the CDC secreted by Trueperella pyogenes, which causes multiple diseases in ruminants. We tested the hypothesis that manipulatingthe mevalonate pathway...
Article
We demonstrate the use of tethered bilayers (tBLMs) as an experimental platform for functional and structural studies of membrane associated proteins by electrochemical techniques. The reconstitution of the cholesterol-dependent cytolysin (CDC) pyolysin (PLO) from Trueperella pyogenes into tBLMs was followed in real-time by electrochemical impedanc...
Article
Full-text available
Defences against the bacteria that usually infect the endometrium of postpartum cattle are impaired when there is metabolic energy stress, leading to endometritis and infertility. The endometrial response to bacteria depends on innate immunity, with recognition of pathogen-associated molecular patterns stimulating inflammation, characterised by sec...
Data
Manipulation of AMPK activity regulates inflammation in endometrial tissue. Ex vivo organ cultures of endometrium were cultured for 6 h in medium containing 0.36 mg/organ glucose with AICAR (a-c: 0, 250, 500, 1000 μM), 1.8 mg/organ glucose with AICAR (d-f: 0, 250, 500, 1000 μM), or 1.8 mg/organ glucose with compound C (g-i: 0, 10, 25, 50 μM). Media...
Data
Impact of inhibiting mTOR on inflammation in endometrial tissue Ex vivo organ cultures of endometrium were cultured in media containing 1.8 mg/organ glucose with (a-c) rapamycin or (d-f) torin-1 (0, 250, 500, 1000 nM) for 6 h followed by medium containing control vehicle or 100 ng/ml LPS for 24 h. At the end of the experiment organ weights were rec...
Data
IGF-1 does not modulate inflammation in endometrial tissue. Ex vivo organ cultures of endometrium were cultured in media containing 1.8 mg/organ glucose with IGF-1 (0, 25, 50, 100 ng/ml) for 6 h, followed by challenge with medium containing control vehicle or 100 ng/ml LPS for 24 h. At the end of the experiment organ weights were recorded and the a...
Article
Full-text available
Interleukin 6 (IL-6), acting via the IL-6 receptor (IL6R) and signal transducer and activator of transcription-3 (STAT3), limits neutrophil recruitment once bacterial infections are resolved. Bovine endometritis is an exemplar mucosal disease, characterized by sustained neutrophil infiltration and elevated IL-6 and IL-8, a neutrophil chemoattractan...
Article
Full-text available
Metabolic changes can influence inflammatory responses to bacteria. To examine whether localized manipulation of the mevalonate pathway impacts innate immunity, we exploited a unique mucosal disease model, endometritis, where inflammation is a consequence of innate immunity. IL responses to pathogenic bacteria and LPS were modulated in bovine endom...
Article
Full-text available
Bacterial infections of the endometrium after parturition commonly cause metritis and endometritis in dairy cattle, and these diseases are important because they compromise animal welfare and incur economic costs, as well as delaying or preventing conception. Here we highlight that uterine infections cause infertility, discuss which bacteria cause...
Article
Full-text available
Endometrial stromal and epithelial cell function is typically studied in vitro using standard two-dimensional monocultures, but these cultures fail to reflect the complex three-dimensional (3D) architecture of tissue. A 3D model of bovine endometrium that reflects the architectural arrangement of in vivo tissue would beneficially assist the study o...
Article
Full-text available
Uterine contamination with bacteria is ubiquitous in the postpartum dairy cow. Nearly one-half of all postpartum dairy cows develop clinical disease resulting in metritis and endometritis, which cause depressed milk production and infertility. The causative links between uterine infection and infertility include a hostile uterine environment, disru...
Article
Full-text available
Uterine contamination with bacteria is ubiquitous in the postpartum dairy cow. Nearly one-half of all postpartum dairy cows develop clinical disease resulting in metritis and endometritis, which cause depressed milk production and infertility. The causative links between uterine infection and infertility include a hostile uterine environment, disru...
Article
Full-text available
OPTIMISING dairy herd fertility and productivity depends on maximising the pregnancy rate (the proportion of inseminations resulting in a pregnancy). However, pregnancy rates in dairy cattle are at an all-time low in many countries, so the study by Bijker and others (2015), summarised on p 411 of this issue of Veterinary Record, makes interesting r...
Article
Full-text available
Dynamin is a GTPase protein that is essential for membrane fission during clathrin-mediated endocytosis in eukaryotic cells. Dynasore is a GTPase inhibitor that rapidly and reversibly inhibits dynamin activity, which prevents endocytosis. However, comparison between cells treated with dynasore and RNA interference of genes encoding dynamin, reveals...
Article
Full-text available
The virulence of many Gram-positive bacteria depends on cholesterol-dependent cytolysins (CDCs), which form pores in eukaryotic cell plasma membranes. Pyolysin (PLO) from Trueperella pyogenes provided a unique opportunity to explore cellular responses to CDCs because it does not require thiol activation. Sublytic concentrations of PLO stimulated ph...
Article
Full-text available
Endometrial epithelial cells are the first line of defense against pathogenic bacteria infecting the uterus. Innate immune responses by these polarized epithelial cells to bacteria and tissue damage are characterized by release of the chemokine (C-X-C motif) ligand 8 (CXCL8) to attract immune cells from the circulation to the site of infection, whe...
Method
Full-text available
Isolation of pure populations of bovine endometrial fibroblasts and epithelial cells from the uterine tissue of slaughtered cows.