Project Details
Description
PEVNET was an innovative research program of biobanks and expertise detecting persistent virus infection as a cause of pathogenic inflammation in type 1 diabetes with the main focus in the detection of persistent enterovirus infection leading to inflammation and tissue damage in the pancreas and its role in mediating the inflammatory response that causes type 1 diabetes.
The work on the detection of viruses (Workpackage 3) was the responsibility of the collaborative research partnership led by key investigators Professor Adrian Bone (Brighton), Professor Noel G Morgan (Exeter) and Professor Alan K Foulis (Glasgow).
Type 1 diabetes is caused by an inflammatory process which damage insulin-producing beta-cells in the pancreas. It is one of the most common chronic diseases and its incidence is rapidly increasing. Due to its complications it causes a significant medical and economic burden to European society.
A causal association between enterovirus and type 1 diabetes has become more and more likely. The aim of the present research programme is to create a new research strategy aligned to a concerted scientific research effort and creation of a network of unique resources which makes it possible to achieve a significant breakthrough in this field.
The main focus was in the detection of persistent enterovirus infection leading to inflammation and tissue damage in the pancreas and its role in mediating the inflammatory response that causes type 1 diabetes.
The goal was to take the critical steps towards therapeutic translation of research findings by employing a novel research design and synergistic networks of excellence based on the combination of a multidisciplinary research strategy and availability of unique biobanks existing in Europe. This research programme will also create a completely new type of biobank which facilitates a wide range of new analyses of fresh tissues.
The programme included a strong translational component which facilitates the ongoing efforts to develop vaccines against diabetogenic enteroviruses and other targeted therapies. The program also had a wider impact on the entire field of research on pathogen-disease associations, since the same innovative research strategy could be applied to other diseases as well.
Altogether, this research program took full advantage of the excellent biobank networks and a long tradition in biomedical and clinical research in Europe and created an exceptional opportunity to take the final steps towards proving causality in the enterovirus-diabetes association.
The work on the detection of viruses (Workpackage 3) was the responsibility of the collaborative research partnership led by key investigators Professor Adrian Bone (Brighton), Professor Noel G Morgan (Exeter) and Professor Alan K Foulis (Glasgow).
Type 1 diabetes is caused by an inflammatory process which damage insulin-producing beta-cells in the pancreas. It is one of the most common chronic diseases and its incidence is rapidly increasing. Due to its complications it causes a significant medical and economic burden to European society.
A causal association between enterovirus and type 1 diabetes has become more and more likely. The aim of the present research programme is to create a new research strategy aligned to a concerted scientific research effort and creation of a network of unique resources which makes it possible to achieve a significant breakthrough in this field.
The main focus was in the detection of persistent enterovirus infection leading to inflammation and tissue damage in the pancreas and its role in mediating the inflammatory response that causes type 1 diabetes.
The goal was to take the critical steps towards therapeutic translation of research findings by employing a novel research design and synergistic networks of excellence based on the combination of a multidisciplinary research strategy and availability of unique biobanks existing in Europe. This research programme will also create a completely new type of biobank which facilitates a wide range of new analyses of fresh tissues.
The programme included a strong translational component which facilitates the ongoing efforts to develop vaccines against diabetogenic enteroviruses and other targeted therapies. The program also had a wider impact on the entire field of research on pathogen-disease associations, since the same innovative research strategy could be applied to other diseases as well.
Altogether, this research program took full advantage of the excellent biobank networks and a long tradition in biomedical and clinical research in Europe and created an exceptional opportunity to take the final steps towards proving causality in the enterovirus-diabetes association.
Key findings
Growing evidence suggested that there was a causal association between persistent enterovirus (EV) infection and development of inflammation that ultimately led to type 1 diabetes (T1D). The EU-funded PEVNET (Persistent virus infection as a cause of pathogenic inflammation in type 1 diabetes - An innovative research program of biobanks and expertise) project studied this potential association.
Persistent EV infections are likely to be regulated by genes that modify the host's immune response against Evs. Researchers therefore performed immunohistochemistry and reverse transcription polymerase chain reaction to detect Evs in the pancreas of T1D patients. The same samples tested positive for actively replicating the virus, thereby indicating progression of EV persistence.
PEVNET scientists analysed T1D patients and controls for their innate immune responses to Evs. Varying EV strains differed in their ability to induce such responses. Mechanisms by which Evs can evade the host immune system were also identified. Coxsackievirus strains' ability to induce innate immune system responses differed, mediated by their interaction with plasmocytoid dendritic cells. An EV receptor, chimeric antigen receptor, was mainly expressed in beta cells, while being less abundant in other pancreas cell types.
Analysis of the cellular infiltrate in the pancreas, coupled with identification of the molecular targets of anti-EV cytotoxic T cell responses revealed the nature and extent of pancreatic inflammation during EV infection and its impact on pancreas morphology and function.
Results from genotyping samples from T1D patients, pre-diabetic subjects and control subjects suggested that genetic variants located in two distinct loci affect the course of EV infection. This may indicate a potential pathogenic mechanism leading to T1D in genetically susceptible subjects infected with Evs.
Vaccination for EV-induced diabetes was analysed in animal models and in clinical treatment trials. Virus-like EV particles (VLPs) were produced and purified. A VLP-based EV vaccine was strongly immunogenic in mice, and VLPs worked well as antigens in antibody assays.
An effective vaccine deployed in early childhood could prevent EV infection and T1D. Combined with antiviral agents, this approach could be delivered at low cost but with major social and economic benefits. PEVNET therefore represents a seismic step in efforts to improve the health of the population of the EU and beyond.
Persistent EV infections are likely to be regulated by genes that modify the host's immune response against Evs. Researchers therefore performed immunohistochemistry and reverse transcription polymerase chain reaction to detect Evs in the pancreas of T1D patients. The same samples tested positive for actively replicating the virus, thereby indicating progression of EV persistence.
PEVNET scientists analysed T1D patients and controls for their innate immune responses to Evs. Varying EV strains differed in their ability to induce such responses. Mechanisms by which Evs can evade the host immune system were also identified. Coxsackievirus strains' ability to induce innate immune system responses differed, mediated by their interaction with plasmocytoid dendritic cells. An EV receptor, chimeric antigen receptor, was mainly expressed in beta cells, while being less abundant in other pancreas cell types.
Analysis of the cellular infiltrate in the pancreas, coupled with identification of the molecular targets of anti-EV cytotoxic T cell responses revealed the nature and extent of pancreatic inflammation during EV infection and its impact on pancreas morphology and function.
Results from genotyping samples from T1D patients, pre-diabetic subjects and control subjects suggested that genetic variants located in two distinct loci affect the course of EV infection. This may indicate a potential pathogenic mechanism leading to T1D in genetically susceptible subjects infected with Evs.
Vaccination for EV-induced diabetes was analysed in animal models and in clinical treatment trials. Virus-like EV particles (VLPs) were produced and purified. A VLP-based EV vaccine was strongly immunogenic in mice, and VLPs worked well as antigens in antibody assays.
An effective vaccine deployed in early childhood could prevent EV infection and T1D. Combined with antiviral agents, this approach could be delivered at low cost but with major social and economic benefits. PEVNET therefore represents a seismic step in efforts to improve the health of the population of the EU and beyond.
| Acronym | PEVNET |
|---|---|
| Status | Finished |
| Effective start/end date | 1/01/11 → 30/06/16 |
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