Towards a standardised cross-sectoral data access agreement template for research: a core set of principles for data access within trusted research environments.

Introduction: Trusted Research Environments (TREs) are secure computing environments that provide access to data for approved researchers to use in studies that can save and improve lives. TREs rely on Data Access Agreements (DAAs) to bind researchers and their organisations to the terms and conditions of accessing the infrastructure and data use. However, DAAs can be overly lengthy, complex, and can contain outdated terms from historical data sharing agreements for physical exchange of data. This is often cited as a cause of significant delays to legal review and research projects starting. Objectives: The aim was to develop a standardised DAA optimised for data science in TREs across the UK and framed around the 'Five Safes framework' for trustworthy data use. The DAA is underpinned by principles of data access in TREs, the development of which is described in this paper. Methods: The Pan-UK Data Governance Steering Group of the UK Health Data Research Alliance led the development of a core set of data access principles. This was informed by a benchmarking exercise of DAAs used by established TREs and consultation with public members and stakeholders. Results: We have defined a core set of principles for TRE data access that can be mapped to a common set of DAA terms for UK-based TREs. Flexibility will be ensured by including terms specific to TREs or specific data/data owners in customisable annexes. Public views obtained through public involvement and engagement (PIE) activities are also reported. Conclusions: These principles provide the foundation for a standardised UK TRE DAA template, designed to support the growing ecosystem of TREs. By providing a familiar structure and terms, this template aims to build trust among data owners and the UK public and to provide clarity to researchers on their obligations to protect the data. Widespread adoption is intended to accelerate health data research by enabling faster approval of projects, ultimately enabling more timely and effective research.

Galectin-3 binds Neisseria meningitidis and increases interaction with phagocytic cells.

Galectin-3 is expressed and secreted by immune cells and has been implicated in multiple aspects of the inflammatory response. It is a glycan binding protein which can exert its functions within cells or exogenously by binding cell surface ligands, acting as a molecular bridge or activating signalling pathways. In addition, this lectin has been shown to bind to microorganisms. In this study we investigated the interaction between galectin-3 and Neisseria meningitidis, an important extracellular human pathogen, which is a leading cause of septicaemia and meningitis. Immunohistochemical analysis indicated that galectin-3 is expressed during meningococcal disease and colocalizes with bacterial colonies in infected tissues from patients. We show that galectin-3 binds to N. meningitidis and we demonstrate that this interaction requiresfull-length, intact lipopolysaccharide molecules. We found that neither exogenous nor endogenous galectin-3 contributes to phagocytosis of N. meningitidis; instead exogenous galectin-3 increases adhesion to monocytes and macrophages but not epithelial cells. Finally we used galectin-3 deficient (Gal-3(-/-) ) mice to evaluate the contribution of galectin-3 to meningococcal bacteraemia. We found that Gal-3(-/-) mice had significantly lower levels of bacteraemia compared with wild-type mice after challenge with live bacteria, indicating that galectin-3 confers an advantage to N. meningitidis during systemic infection.

New insights into pathogen recognition.

The Society for General Microbiology (SGM) Spring Conference covers a range of topics of microbiology and comprises mixed sessions including symposia, workshops, debates, offered papers and invited presentations from international experts. This year the SGM Conference was held 11-14 April 2011 at the Harrogate Conference Centre in Harrogate, Yorkshire (UK). The main aim of the meeting is generally to provide a variety of programs that reflect current knowledge on different topics and introduce the recent advances in general and applied microbiology. Aspects of microbial recognition and interaction with the host immune response were addressed during a session of the meeting, where leaders in the field highlighted how the immune system is designed to recognize and destroy microorganisms by detecting microbial signature molecules (pathogen-associated molecular patterns) via interaction with specific receptors. This article focuses on the current research on pathogen recognition by the host through the interaction with surface structures present on microorganisms, with particular interest on the family of lectins, an emerging area in the understanding of infectious diseases. Discovering the mechanisms used by bacteria to survive in the host environment and at the same time elucidating the processes by which the immune system interacts with pathogens is vital for the development of vaccines and the design of new therapies.

Serum and urinary levels of IL-18 and its inhibitor IL-18BP in systemic lupus erythematosus.

Overproduction of inflammation-related cytokines plays an important role in systemic lupus erythematosus (SLE). A crucial cytokine is IL-18, a member of the IL-1 family involved in the regulation of both innate and acquired immune responses. The aim of this study was to evaluate free IL-18 levels in the serum and urine of SLE patients, in order to establish their relationship with other biomarkers of disease activity. Serum and urine levels of IL-18 and IL-18BP were measured by ELISA in 50 SLE patients and in 32 healthy subjects; free IL-18 was calculated using the law of mass action. Serum levels of total IL-18, IL-18BP and free IL-18 were higher in SLE patients than in healthy controls. Total and free serum IL-18 levels were higher in patients with active disease (with nephritis or active non-renal disease), and correlated with the ECLAM score. Urinary levels of total and free IL-18 were higher in patients than in controls, but did not correlate with disease activity. The data collected in this study show that increased levels of both IL-18 and its natural inhibitor IL-18BP, characterise SLE. Despite the overproduction of IL-18BP, free IL-18 is still significantly higher in SLE patients than in controls, and its serum levels are a marker of disease activity.

Transcellular passage of Neisseria meningitidis across a polarized respiratory epithelium.

Neisseria meningitidis is a major cause of sepsis and meningitis but is also a common commensal, present in the nasopharynx of between 8 and 20% of healthy individuals. During carriage, the bacterium is found on the surface of the nasopharyngeal epithelium and in deeper tissues, while to develop disease the meningococcus must spread across the respiratory epithelium and enter the systemic circulation. Therefore, investigating the pathways by which N. meningitidis crosses the epithelial barrier is relevant for understanding carriage and disease but has been hindered by the lack of appropriate models. Here, we have established a physiologically relevant model of the upper respiratory epithelial cell barrier to investigate the mechanisms responsible for traversal of N. meningitidis. Calu-3 human respiratory epithelial cells were grown on permeable cell culture membranes to form polarized monolayers of cells joined by tight junctions. We show that the meningococcus crosses the epithelial cell barrier by a transcellular route; traversal of the layer did not disrupt its integrity, and bacteria were detected within the cells of the monolayer. We demonstrate that successful traversal of the epithelial cell barrier by N. meningitidis requires expression of its type 4 pili (Tfp) and capsule and is dependent on the host cell microtubule network. The Calu-3 model should be suitable for dissecting the pathogenesis of infections caused by other respiratory pathogens, as well as the meningococcus.

IL-18 activity in systemic lupus erythematosus.

Interleukin-18 (IL-18) is an inflammation-related cytokine that plays a central role both in innate defense reactions and in Th1 activation and specific immune responses. Increased levels of IL-18 can be detected in biological fluids and organs of individuals affected by several autoimmune pathologies, as well as in autoimmune animal models. In this review, the role of IL-18 in systemic lupus erythematosus (SLE) is critically examined, including its possible role in the pathogenesis of disease. In SLE, increased levels of IL-18 have been found in serum/plasma of affected persons, which positively correlated with disease severity. The possibility that circulating IL-18 levels are predictive of renal damage has been proposed, suggesting that IL-18 may be a prognostic marker of renal involvement useful to identify patients at risk of renal failure. The evaluation of urinary levels of free active IL-18 indeed suggests a correlation with the degree of renal involvement. The possible pathogenic role of IL-18 in lupus has been studied in a mouse model of progressive disease, which makes possible the identification, at the level of the different affected organs, of IL-18 changes preceding disease development and those appearing after disease onset. It can be concluded that IL-18 has a multifaceted role in autoimmune lupus, being apparently involved both in the effector phases of the late organ damage and, in some organs, in the initial pathogenic events. Therapeutic strategies targeting IL-18 in autoimmunity are under development.

Innate defence functions of macrophages can be biased by nano-sized ceramic and metallic particles.

Nano-sized particles of ceramic and metallic materials are generated by high-tech industrial activities, and can be generated from worn-out replacement and prosthetic implants. The interaction with the human body of such nanoparticles has been investigated, with a particular emphasis on innate defence mechanisms. Human macrophages (PMA-differentiated myelomonocytic U-937 cells) were exposed in vitro to non-toxic concentrations of TiO(2), SiO(2), ZrO(2), or Co nanoparticles, and their inflammatory response (expression of TLR receptors and co-receptors, and cytokine production) was examined. Expression of TLR receptors was generally unaffected by exposure to the different nanoparticles, except for some notable cases. Exposure to nanoparticles of ZrO(2) (and to a lesser extent TiO(2)), upregulated expression of viral TLR receptors TLR3 and TLR7. Expression of TLR10 was also increased by TiO(2) and ZrO(2) nanoparticles. On the other hand, TLR9 expression was decreased by SiO(2) nano-particles, and expression of the co-receptor CD14 was inhibited by Co nanoparticles. Basal and LPS-induced production of cytokines IL-1beta, TNF-alpha, and IL-1Ra was examined in macrophages exposed to nanoparticles. SiO(2) nanoparticles strongly biased naive macrophages towards inflammation (M1 polarisation), by selectively inducing production of inflammatory cytokines IL-1beta and TNF-alpha. SiO(2) nanoparticles also significantly amplified the inflammatory phenotype of LPS-polarised M1 macrophages. Other ceramic nanoparticles had little influence on cytokine production, either in resting macrophages, or in LPS-activated cells. Generally, Co nanoparticles had an overall pro-inflammatory effect on naive macrophages, by reducing anti-inflammatory IL-1Ra and inducing inflammatory TNF-alpha. However, Co nanoparticles reduced production of IL-1beta and IL-1Ra, but not TNF-alpha, in LPS-polarised M1 macrophages. Thus, exposure to different nanoparticles can modulate, in different ways, the defence/inflammatory capacities of macrophages. A thorough analysis of these biasing effects may shed light on the mechanisms of pathogenesis of several diseases based on dysregulation of the immune response (allergies, autoimmunity, tumours).