Dr Rachel Simmonds

Research Interests

Inflammation is an essential immediate response to infection and is a direct outcome of innate immune system activation. Components of pathogens are recognised by cellular Toll-like receptors which go on to activate a complex series of signalling pathways, ultimately resulting in the coordinated production of inflammatory mediators such as cytokines, chemokines and intracellular proteins. It has been known for some time that the production of these mediators is controlled by the level of gene transcription and by changes to mRNA stability.

My research is particularly focussed on understanding the role of regulated protein translation in the innate immune response. This layer of post-transcriptional regulation is vitally important to achieving appropriate inflammation, but it is not yet well understood.  I am using novel approaches to uncover the mechanisms involved in order to understand the host response to pathogens and how they exploit this system to avoid immune surveillance and cause disease.

Gene-specific translational control by mycolactone, a mycobacterial virulence factor

Buruli ulcer is a serious skin infection that affects some of the poorest communities in the world. It causes massive debilitating skin ulcers, often leading to disfigurement or amputation. This is due to a substance released by the infecting bacteria (Mycobacterium ulcerans) called mycolactone. This lipid-like substance is responsible for the formation of necrotic ulcers and their characteristic lack of inflammation. My group was the first to study the effects of mycolactone on cytokine production by isolated immune cells and showed that it potently inhibits this function.

Following on from this we recently demonstrated that mycolactone is a selective inhibitor of translation. It specifically targets the production of inflammatory mediators including TNF, IL-6 and COX-2, but many other proteins escape. An investigation to define the precise mechanism by which mycolactone exerts this unique activity has recently been funded by the Wellcome Trust. The working hypothesis is that mycolactone acts on a novel translation-activating pathway involving a cis-acting mRNA element and trans-acting factors. Current collaborations to investigate this function include

• Pamela Small - immunosuppressive functions of mycolactone
• Anne Willis - mechanism of mycolactone-dependent translational control

MicroRNAs in the innate immune response

MicroRNAs (miRNAs) are short ~22nt RNA molecules that are thought to regulate the expression of as many as one half of all human genes. A number of miRNAs have been described as being induced following exposure of myeloid cells to lipopolysaccharide (LPS; the gram-positive microbial cell wall component) including miR-146a, miR-146b and miR-155. However, since screens for miRNAs of this type have mostly been performed in murine cells or in human cell lines (both known to have important functional differences to primary human cells) this might not represent an exhaustive list.

Recently a miRNA microarray was performed, with the potential to pick up more than 700 human miRNAs. As a result, two novel miRNAs were identified that currently have no function ascribed in the literature. The function of these miRNAs is currently under investigation. Early data suggests that one of the functions of anti-inflammatory IL-10 is to modulate miRNA expression. Current collaborations to investigate miRNA functions include

• Elena Vigorito - the effect of miR-155 knockout on development of arthritis
• Martin Bushell - differential regulation of microRNAs
• Mark Lindsay - microRNAs in innate immunity

Publications

Simmonds RE, Lali FV, Smallie T, Small PLC and Foxwell BM. Mycolactone inhibits monocyte cytokine production by a post-transcriptional mechanism J Immunol 2009: 182; 2194-2202

Sacre SM, Lo A, Gregory B, Simmonds RE, Williams L, Feldmann M, Brennan FM, Foxwell BM. Inhibitors of TLR8 reduce TNF production from human rheumatoid synovial membrane cultures.  J Immunol 2008: 181; 8002-9

Simmonds RE and Foxwell BM. NF-kB and its relevance to arthritis and inflammation (Review). Rheumatology (Oxford) 2008: 47; 584-90

White SJ, Simmonds RE, Lane DA and Baker AH. Efficient isolation of peptide ligands for the endothelial cell protein C receptor (EPCR) using candidate receptor phage display biopanning. Peptides 2005: 26; 1264-1269

Biguzzi E, Razzari C, Lane DA, Castaman G, Cappellari A, Bucciarelli P, Fontana G, Margaglione M, D’Andrea G, Simmonds RE, Rezende SM, Preston R, Prisco D, Faioni EM for the PROSIT. Molecular diversity and thrombotic risk in Protein S deficiency. The PROSIT study. Hum Mut 2005: 25; 259-269

Rezende SM, Simmonds RE and Lane DA. Coagulation, inflammation and apoptosis: different roles for protein S and the protein S-C4b binding protein complex (Review). Blood 2004: 103; 1192-1201

Rance J, Follows GA, Cockerill PN, Bonifer C, Lane DA, Simmonds RE.  Regulation of the human endothelial cell protein C receptor gene promoter by multiple Sp1 binding sites. Blood 2003:101; 4393-4401

Mille-Baker B, Rezende S, Simmonds RE, Lane DA and Laffan M. Deletion or replacement of the second EGF-like domain of protein S results in loss of APC cofactor activity. Blood 2003: 101; 1416-8

Rezende SM, Razzari C and Simmonds RE. In vitro high level protein S expression after modification of protein S cDNA (letter). Thromb Haemost 2003: 90; 1214-5

Rezende SM, Lane DA, Mille-Baker B, Samama M, Conard J and Simmonds RE. Protein S Gla-domain mutations causing impaired Ca2+-induced phospholipid binding and severe functional protein S deficiency. Blood 2002: 100; 2812-9

Rezende RM, Lane DA, Zöller B, Mille-Baker B, Laffan M, Dahlbäck B and Simmonds RE. Genetic and Phenotypic Variability between Families with Hereditary Protein S Deficiency. Thromb Haemost 2002: 87; 258-65

Simmonds RE and Lane DA. The Endothelial Cell Protein C Receptor: A Candidate Genetic Risk Factor for Thrombosis (Invited Commentary). Thromb Haemost 2001: 86; 939-41

Simmonds RE, Hermida J, Rezende SM, Lane DA. Haemostatic risk factors in arterial thrombosis (Review). Thromb Haemost 2001: 86; 374-85

Gandrille S, Borgel D, Sala N, Espinosa-Parrilla Y, Simmonds R, Rezende S, Lind B, Mannhalter I, Pabinger P, Reitsma PH, Formstone C, Cooper DN, Saito H, Suzuki K, Bernardi F, Aiach M.  Protein S Deficiency: A Database of Mutations - Summary of the First Update.  Thromb Haemost 2000: 84; 918

Simmonds RE and Lane DA.  Structural and functional implications of the intron/exon organisation of the human endothelial cell protein C/activated protein C receptor (EPCR) gene.  Comparison with the structure of CD1/Major Histocompatibility Complex alpha1 and alpha2 domains.  Blood 1999: 94; 632-41

Simmonds RE, Ireland H, Lane DA, Zöller B, García de Frutos P and Dahlbäck B . Clarification of the risk of venous thrombosis associated with hereditary protein S deficiency by investigation of a large kindred with a characterised gene defect.  Ann Int Med 1998; 128; 8-14

Gandrille S, Borgel D, Ireland H, Lane DA, Simmonds R, Reitsma PH, Mannhalter C, Pabinger I, Saito H, Suzuki K, Formstone C, Cooper DN, Espinosa Y, Sala N, Bernardi F, Aiach M.  Protein S deficiency: a database of mutations.  For the plasma coagulation inhibitors subcommittee of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis.  Thromb Haemost 1997; 77; 1201-14

Simmonds RE, Zöller B, Ireland H, Thompson E, García de Frutos P, Dahlbäck B and Lane DA.  Genetic and phenotypic analysis of a large (122 member) protein S-deficient kindred provides an explanation for the familial coexistence of type I and type III plasma phenotypes.  Blood 1997; 89; 4364-70

Simmonds RE, Ireland H, Kunz G, Lane DA and the Protein S Study Group.  Identification of 19 protein S gene mutations in patients with phenotypic protein S deficiency and thrombosis.  Blood 1996; 88; 4195-204

Departmental Duties

FHMS Research Events Coordinator

Local Ambassador for the Biochemical Society