Diagnostics & Imaging Week International Correspondent
LONDON — People’s risks of succumbing to four major infectious diseases are influenced by a change in a single amino acid, in a protein that helps to stimulate the immune response to infections.
The genetic mutation that causes this change is a single nucleotide polymorphism (SNP) in the gene encoding a protein called Mal. People with a single copy of the SNP are best off: they have half the risk of suffering from malaria, pneumococcal disease, tuberculosis and bacteraemia compared to those who have two copies of the SNP, and those who have none.
Mal occupies a central position in the signaling pathways that become active once a pathogen interacts with receptors found on the surface of cells of the immune system. Once these receptors, called Toll-like receptors (TLRs), become activated, they trigger pathways within the cells leading to an inflammatory immune response.
Luke O’Neill, professor of molecular immunology and head of the School of Biochemistry and Immunology at Trinity College Dublin (Dublin, Ireland), told Diagnostics & Imaging Week’s sister publication BioWorld International: “The fact that Mal has a determining role for infectious disease adds weight to the idea that drugs that can manipulate the TLR system will be useful.”
Many companies, he added, including Opsona Therapeutics (Dublin), which he helped to found, are following such a strategy. Products that activate TLRs may help to make vaccines more effective, or make it possible to produce vaccines against tumors; conversely, blocking TLRs may help damp down the immune response in infections such as malaria and sepsis, where many people die as a result of an over-vigorous immune reaction.
O’Neill, together with Adrian Hill, professor of human genetics at the Wellcome Trust Centre for Human Genetics at the University of Oxford, and their colleagues, report their finding of the SNP in the gene encoding Mal in Nature Genetics (advance online publication, Feb. 25). The title of the paper is: “A Mal functional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria and tuberculosis”.
Hill and O’Neill began collaborating over three years ago, when Hill was well advanced in searching for genetic variants that influenced susceptibility to infectious diseases. The pair had agreed that the genes encoding the TLRs and the molecules involved in subsequent signaling would be a fertile hunting ground for such variations—particularly since Mal was known to react to a product of the malaria parasite.
Hill and his colleagues went on to identify an SNP in the gene encoding Mal, which was consistently found less commonly in people with infectious diseases. This SNP changed the normal serine at position 180 in the protein to a leucine.
The next step was to analyze whether this SNP was absent or present in one or two copies in 6,106 individuals with four different diseases. The groups analyzed were two UK populations of European ancestry with invasive pneumococcal disease; a Kenyan population with bacteremia; three populations with malaria (from the Gambia, Kenya and Vietnam); and two populations with tuberculosis (from Algeria and several countries in West Africa). Control groups were also analyzed in each setting.
Taken overall, there was a clear association between being heterozygous for the SNP in question, and being protected against all four infectious diseases: the risk in heterozygotes was halved. Hill said: “This appears to be the first example of a single genetic variant that influences susceptibility to several major infectious diseases.”
Further investigations by O’Neill and his colleagues showed that Mal with leucine at position 180 — the mutant form — was inactive, and unable to trigger the desired response in the cell.
O’Neill said: “We found that those who were heterozygous for the SNP were those who were protected against disease. But people who had either two copies of the SNP, or no copies of the SNP, were at greater risk of disease. We think this is because those without any functioning Mal are unable to mount an immune response and they die of infections, while the immune response of those who have no copies of the SNP goes into overdrive, and they die of ‘friendly fire’.”
In the long term, he added, it will be possible to identify people who are at greater risk of succumbing to these infections, and tailor their treatment accordingly — either with more aggressive antibiotics, or with drugs that could modulate Mal.
Future research will include looking at whether the same SNP plays a role in susceptibility to a range of autoimmune diseases, such as rheumatoid arthritis, inflammatory bowel disease and lupus.