Some hapless people infected with the leprosy bug (Mycobacterium leprae) manifest its frightful, irreversible signs and symptoms; others, equally exposed to the pathogen, get off scot-free. How come?
The scientists who succeed in grabbing this immunological brass ring will win a "big deal," foresees genomicist/immunologist Thomas Hudson at McGill University in Montreal. Leprosy itself is a very big deal. The World Health Organization puts at 11.5 million the number of lepers in 91 countries worldwide, and their numbers increase by 700,000 a year.
Symptoms of leprosy include pigmented skin lesions and permanent nerve damage leading to numbness and paralysis. If left untreated, as it often is for lack of a pain reflex, the disease may result in gross facial and body disfiguration, including loss of fingers, toes, feet and hands. The M. leprae bacteria are transmitted through direct personal contact or contaminated respiratory droplets. Currently, 60 percent of new cases present with so-called paucibacillary leprosy, featuring few skin lesions and absence of detectable M. leprae organisms in those lesions
In past centuries, leprosy was rife worldwide, especially in Europe. Now, Hudson observed, "It's still very common in India, Asia, Brazil and Africa." He pointed out, "Effective chemotherapeutic treatment is available for leprosy, and the only known M. leprae reservoir of biological significance is humans. Yet the worldwide incidence of leprosy has shown little decrease over the last 15 years."
Hudson is co-senior author of a paper to appear in the March 2003 issue of Nature Genetics. Its title: "Chromosome 6q25 is linked to susceptibility to leprosy in a Vietnamese population." The article's other co-senior author is molecular geneticist/immunologist Erwin Schurr, at McGill.
"This discovery," observed Schurr, "will now allow us to study how the gene works, and how it influences the infectious process. This is an important step toward the development of innovative prevention and treatment strategies for leprosy."
"Our genome-scanning approach in this report," Hudson told BioWorld Today, "was state-of-the-art genetic linkage analysis. Now we're showing that leprosy is a common disease in the Third World, and that we're close to finding a susceptibility gene that makes people vulnerable to it. There's a lot of speculation as to what that gene might do, and we're going to find out, and how to use it down the road."
Putative Susceptibility Gene May Surpass Leprosy
"We're seeing that humans as well as animals exhibit genes that predispose to infection," Hudson said. "In this case we're very close to a leprosy gene, and this will have impact for 700,000 new cases yearly in the world. Leprosy is a very debilitating chronic disease of the nervous system, so such a gene will be useful. Perhaps it will prove important in other types of infections, which are even more common, like tuberculosis, leishmaniasis, malaria or whatever. We now have to go back and do the next round of experiments."
So far, two chromosomal genomic neighborhoods stand out as candidate susceptibility genes. The locus of chromosome 10's short arm (10p13) was surveyed two years ago in India by researchers at Oxford University. (See BioWorld Today, April 2, 2001.)
"Chromosome 6 is the hottest one," Hudson observed. "A small region within 50 to 100 genes, and a lot of the Vietnamese families have been screened already at the genome center here. The process will move very fast. All the good candidate susceptibility genes are being looked at in parallel at this point." Hudson's genome-wide scan initially tested 86 families from southern Vietnam, including 205 siblings affected with leprosy. They confirmed the likelihood of finding a susceptibility gene on chromosome 6p25, and verified this analysis in an independent panel of 208 Vietnamese families. Of seven microsatellite markers underlying the linkage peak, alleles of two markers showed strong evidence for association with leprosy.
"These families have multiple cases of members with the disease," Hudson noted. "And what we look for in these families are markers from all the chromosomes. There are about 400 genetic markers covering the human genome included in the scan, and we see whether both siblings are infected, how much sharing they have of genetic markers. Twin studies and family segregation analyses suggest the existence of a strong genetic component for susceptibility to leprosy in human populations.
"Brothers and sisters share 50 percent of the genome markers," he recounted. "Half of the chromosomes are identical between brothers and sisters. But where there's a disease gene, when siblings share the disease, what happens is that brothers and sisters share 60, 70, 80, 90 percent of the genome, because that's a signature of where the disease gene is. So by looking at the chromosome we identified on this block of chromosome 6, for example, that siblings who have the disease often share this region caused by the presence of that susceptibility gene. We could only be wrong in one in a million cases happening by chance," Hudson said.
6p25 Gets First Licks At Low-Lying Gene
"It was even surprising that there would be a major gene for susceptibility to leprosy. We thought there may be many minor genes with small effect, but what this paper has actually shown is that there is at least one major gene, which has a big effect on predisposition for infection. We also detected the presence of a gene there on that chromosome 10p13. It's not as strong, so right now we're putting all our energy on the 6p25, which is the stronger. When that's done we'll move on to 10.
"We're hoping to pinpoint the chromosome 6 gene proper in one to two years," Hudson allowed. "Then what to make of it will depend on what the gene does - if it has anything to do with inflammation or how the bacteria binds to cells. So we might try to use that information to develop vaccines, or other ways to treat patients - not just with antibiotics but methods to stimulate the immune system. The knowledge that we'll gain from that gene will help devise new strategies for treatment."
Hudson observed, "Canada is investing $300 million in functional genomics and human genetics for the next five years so we can be competitive in biotechnology. About $15 million," he concluded, "will go for studying susceptibility to infectious diseases."