Why some children never got TB while others fell prey remains one of the most vexing puzzles in the annals of infectious disease. Today, according to the World Health Organization, TB infects roughly one-third of the world's population--that's 2.4 billion people--but in most, the infection remains harmlessly latent. Only 10 percent go on to develop active, life-threatening disease, at the rate of eight million a year. TB kills two to three million annually--surely a low estimate, says Harvard School of Public Health Dean Barry Bloom, who has studied the bacterium for almost four decades.
Because all the Lübeck children were equally well cared for, scientists suspected that genetic differences, not environmental stresses, were pivotal in determining who resisted TB, who succumbed, and who struck a truce with the bacterium. Numerous studies have validated that hunch. However, many genes probably contribute to TB immunity, the research shows, and with no good laboratory animal model for the disease, the quest to understand the genetic underpinnings of TB resistance has been a long, exasperating struggle.
Now, Igor Kramnik, assistant professor of immunology and infectious diseases at HSPH, Dean Bloom, and their colleagues have astonished the tuberculosis-research community with the discovery of a single gene that, in mice, determines susceptibility or resistance.
In a commentary accompanying the researchers' April 7, 2005, paper in Nature, reviewers called this milestone an "unexpected gift"--one that will surely lead to "more exciting biology in an area of immense interest for global health."
If an already identified analogous gene in humans proves to have the same powers, Kramnik explains, scientists might be able to design drugs that mimic or stimulate the activity of the resistance gene. And doctors might be able to predict which of their patients who test positive for TB infection are at risk of developing active disease and channel them toward preventive interventions, sparing the rest needless treatment.
microbe meets host
What scientists know so far is that, right away, the bacterium sneaks inside large immune cells called macrophages, whose job is to gobble up invading microbes. Other immune cells wall off the infected macrophages, forming hard encasements called tubercles or granulomas.
In a latent infection, TB bacteria remain inactive. Hunkered down inside the granulomas, they cause little harm. But for reasons not yet known, the bacteria occasionally reactivate, provoking the immune system to overreact in a self-destructive inflammatory response. The granulomas burst open in an untidy form of death known as necrosis, forming cavities in the lungs that ooze bacteria. These pathogens invade the airways and ride the droplets of a cough, potentially infecting scores of people at one time.
Unlike most other kinds of bacteria, the TB bacterium grows slowly and produces no toxins to destroy its host's tissues directly. Its unusual ability to lie in wait and then infect multitudes is "probably the single most important factor in the evolution of TB," Kramnik says, and the reason it's considered the most successful of all bacterial pathogens in humans.
But considering that mice, much like people, vary greatly in their ability to resist TB, Kramnik suspected that some as-yet-undiscovered genetic variants of laboratory mice might have cavities. In 1996, a determined search finally paid off when Kramnik observed nasty lung cavities similar to those in TB-susceptible humans in a single inbred mouse strain among hundreds that were readily available from the Jackson Laboratory, in Maine, the world's leading producer of laboratory mice.
Next, Kramnik set out to determine whether this trait was genetically controlled. He crossbred his highly TB-susceptible mouse strain with a genetically distinct strain that staunchly resisted infection. To his surprise, 25 percent of the crossed offspring developed lung cavities, just as human TB victims do--a pattern of inheritance suggesting that lung-cavity formation might be controlled by a single gene. Then, Kramnik embarked on a hunt for precise differences in the two strains' genetic material.
Early on, Kramnik's lab had identified a segment of mouse chromosome 1 that distinguished resistant from susceptible mice. Given that the mouse genome had already been sequenced by researchers elsewhere, the HSPH team had high hopes for identifying all the genes within this region quickly. But as it turned out, the region fell within a long, seemingly nonsensical stretch of DNA that had thus far eluded sequencing. So the researchers set about the tedious work of genetically dissecting this stretch. Eventually they isolated a gene expressed in macrophages and gave it a name: Ipr1, short for intercellular pathogen resistance.
Next, they needed proof that this gene controlled TB infection in the lungs. After switching the gene in the two types of mice, they observed that, indeed, the susceptible mice could now better resist TB, while resistant mice became more susceptible. "We were amazed at the difference one gene made," Kramnik says.
Molecular tests showed that Ipr1 dictates the type of death macrophages undergo, toggling between the normal, orderly process called apopotosis and a chaotic, pathological necrosis. In certain people, Kramnik speculates, the gene's activity must somehow downshift after years of latent infection, leaving macrophages to suffer the disorderly death that incites a vicious inflammatory reaction in lung tissue.
That role, Bloom says, concerns the built-in, or "innate," immune system. Whereas organisms develop adaptive immunity only after being exposed to a microbial invader, they possess innate immunity right from the start. No prior encounter with invaders is required.
"It's intriguing that this profoundly important new gene doesn't control the immune cells that drive the adaptive response, the B and T cells," Bloom observes. "Igor's gene controls macrophages, which are designed to capture and kill bacteria as the first line of defense. That makes Ipr1 one of a very few genes known to control innate immunity." Bloom says learning more about such genes could have a far-reaching impact on infectious-disease research.
As for the quest for better TB drugs and vaccines, the discovery by Kramnik and company is unlikely to languish in research latency.
"We have a dire need for an animal model that mimics latent TB infection in humans," says Christine Sizemore, the acting section head in charge of TB at the National Institute of Allergy and Infectious Diseases (NIAID).
"This is an example where mouse studies give you new hypotheses to test in humans. Since this finding has the potential to give us new animal models for vaccine or drug selection, we will speak to our investigators to see how we can integrate this finding into the resources NIAID offers to the TB research community."
One day, a single mouse gene called Ipr1 may help solve TB's enduring mystery.
Cathryn Delude has written about science and health for Scientific American, the Scientist, MIT Tech Talk, and the Boston Globe.
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