Mastering the molecule behind diseases provoked by overactivated immune systems
An EU-funded researcher has learnt more about a molecule that suppresses the activation of the immune system during Salmonella infection, believing it holds the key to finding therapies for diseases that cause overactive immune systems. The molecule SteD in Salmonella infections can prevent the activation of T helper (Th) 1 cells that stimulate the immune system to fight bacterial infections, found the SupaSteD project. Research fellow Ondrej Cerny’s study was carried out at Imperial College, supervised by David Holden, the United Kingdom’s first Regius Professor of Infectious Disease, and supported by the Marie Skłodowska-Curie programme. “We hope that this capacity of SteD could be exploited to treat excessive immune activity in non-related diseases like allergies or Crohn’s disease,” says Cerny. In the process of the research the team had an unexpected breakthrough: they managed to define the biochemical function of a protein that suppresses human tumours.
Painful disorders
There are currently no medical procedures or surgery that can cure Crohn’s disease. Crohn’s disease is an auto-inflammatory disorder associated with excessive Th1 cell activation in which the body’s immune system attacks the gastrointestinal tract. This causes symptoms like abdominal pain, fever and weight loss. It also increases the risk of bowel cancer. There are 78 000 new cases diagnosed in Europe every year: 1.6 million people suffer from it, according to ‘The burden of inflammatory bowel disease in Europe’, published in the Journal of Crohn’s and Colitis. Humans have an innate immune system that attacks anything foreign, frequently recognising molecular signatures that are common to bacteria or viruses. Cerny’s work focused on exploring the way the molecule SteD, a Salmonella virulence protein, affects adaptive immunity. The adaptive immune system is trained over a lifetime to recognise and destroy very specific antigens and learns to discriminate, for example, between bacteria that cause disease and those used in probiotics. During SupaSteD, Cerny considered the activation status of CD4+ T lymphocytes, cells from the adaptive immune system, in mice infected with Salmonella Typhimurium. He compared these with mice infected with the same strain of Salmonella, but which carried a defined mutation – a deletion of the gene encoding SteD. The project identified the crucial amino acids in the SteD sequence required for its function. “SteD derived from Salmonella strains adapted to humans are very well suited for any potential clinical use of SteD,” says Cerny. However, more research will be needed before SteD can be used clinically to develop therapy for immune diseases. One factor that needs further consideration is the project’s finding that the molecule blocks the interaction between dendritic cells and T cells. “That was very unexpected,” he adds. Cerny is now aiming to set up his own research group to study the influence of other bacterial pathogens on adaptive immunity. “The EU funding provided the springboard for me to develop my future career as an independent scientist,” says Cerny, who will publish some of the findings from the SupaSteD project later this year.
Keywords
SupaSteD, Crohn’s disease, overactive immune systems, overactivated immune system, Salmonella infections, SteD, T helper (Th) 1 cells
