Fig. 1: A micrograph of Mycobacetrium leprae, the bacterium responsible for leprosy, which has proved difficult to study by conventional microbiological methods.
© 2010 Jianjun Liu
The symptoms of leprosy—skin lesions and nerve damage—have been recognized since Biblical times, but even today, scientists know few details about the pathology of infection with Mycobacterium leprae (Fig. 1). This is due in large part to the challenges of cultivating this bacterium and the absence of a useful animal model.
As such, indirect strategies may prove more practical, as demonstrated by a recent collaborative study by Singaporean and Chinese groups that examined Han Chinese individuals in order to identify genetic factors that might contribute to susceptibility to this pathogen. “The low diversity of the M. leprae genomic sequence suggests that susceptibility to leprosy is largely due to human host variability,” says Jianjun Liu, one of the leaders of the project at A*STAR’s Genome Institute of Singapore. “Human genetic studies will be able to provide biological insights into this infectious disease, which is hard to study by other means.”
Genome-wide association studies are an effective strategy for identifying risk factors for heritable disorders. In these studies, researchers attempt to identify single-nucleotide sequence variations in the genome that are closely associated with a disease within families or populations. In principle, the same approach can be applied to infectious disease, provided appropriate healthy controls are identified. “The best controls for such a study should be individuals who have been exposed to pathogens but failed to be infected,” says Liu.
His team analyzed nearly half a million sequence variants in each of 706 leprosy patients and 1,225 controls, identifying 16 polymorphisms within seven different genes that appeared to represent true susceptibility factors. Interestingly, variations in four of these genes showed stronger association with the ‘multibacillary’ form of leprosy, which is characterized by elevated counts of bacteria in skin lesions and is therefore thought to be indicative of compromised immune response.
Most of the genes identified were found to be interconnected with a signaling network mediated by risk factor NOD2, a protein that acts as a trigger for early stage immune responses to bacterial infection; three of these genes are also involved with the inflammatory intestinal disorder Crohn’s disease, an association previously considered controversial. “It has long been suggested that mycobacterial infection might be one of the triggers for Crohn’s disease, but this hypothesis has not been accepted by the [scientific] community,” says Liu. “Our findings provide strong genetic evidence.”
Future genomic studies from Liu and his co-workers will further explore details of these associations, as well as the connection between specific genetic risk factors and different clinical subtypes of leprosy.
The A*STAR-affiliated authors in this highlight are from the Genome Institute of Singapore.
