A Harvard School of Public Health researcher is figuring out how tuberculosis bacteria defend themselves so well against immune attack and drug treatment.
Courtney Humphries
As much as one-third of the world’s population is infected with Mycobacterium tuberculosis, the bacteria that cause tuberculosis (TB). Yet relatively little is known about how the organism manages to persist for so long, sometimes for decades, in so many people. Though tuberculosis can be fatal, in most cases the immune system controls the acute infection. However, small numbers of the bacteria are often able to fend off antibiotics and immune attack and remain in the body to cause recurring infections years later.
Sarah Fortune of the Harvard School of Public Health says that the commonly held belief, that the tuberculosis bacteria are “in hiding,” is overly simplistic. She believes that, while in the human body, the bacteria undergo changes in the sequences and the expression of their genes and are able to divide and pass those changes down to the next generation. These changes, she says, keep the bacteria under the immune system’s radar indefinitely and enable them to resist drug treatment.
Harvard School of Public Health researcher Sarah Fortune is uncovering the mysteries of the TB bacteria.
Her lab is deciphering these alterations, which could lead to insight on how to improve treatment and prevent drug resistance, a growing problem among TB patients. “We want to understand what the genes look like and the patterns of mutability,” Fortune says.
Catch in the act
Fortune, assistant professor of immunology and infectious disease, has been running a lab for just about a year, but her approach to studying TB has already garnered a series of awards, including one of the newly launched New Innovator Awards from the National Institutes of Health.
To investigate how the TB bug changes during infection, Fortune’s lab is sequencing the genomes of different strains of TB isolated from patients and comparing them to identify patterns of mutation associated with persistent infection.
The Fortune lab is also opening up a new area of study by looking for possible epigenetic changes in the TB bacteria—modifications in the way the genes are expressed that don’t involve changes to the DNA sequence itself. “There are few examples of epigenetic inheritance in bacteria,” Fortune says. Bacterial DNA does not have the same elaborate structures usually associated with epigenetic control. But Fortune believes that bacteria “could have other ways of generating functional diversity,” such as simpler structural changes to the bacterial DNA that are akin to familiar epigenetic modifications in more-complex organisms.
TB mysteries
Genetic mutations associated with drug resistance are well known in other bacterial pathogens, but TB is less understood, in part because of logistical hurdles; the TB bacteria grow relatively slowly, and studying them requires strict security measures and expensive equipment. Fortune says that part of her approach is to look at mechanisms that other bacteria use to evade the immune system and see if they might also apply to TB.
A better understanding of the bacteria’s behavior during infection could shed light on mechanisms of drug resistance. Fortune, who trained as an infectious-disease doctor before switching to full-time research, says that the emergence of drug-resistant TB is often seen as a failure in treatment on the part of clinicians or a lack of drug compliance on the part of patients. “It’s not clear whether it’s all just institutional failure or whether it is similar to other bacterial infections, where there are subpopulations more likely to become drug resistant,” says Fortune. Some infectious bacteria, for instance, have subpopulations that mutate very rapidly and so are more likely to acquire resistance. M. tuberculosis could be one such bacterium, Fortune says.
William Jacobs, a TB researcher at the Albert Einstein College of Medicine in New York, says that Fortune’s work is especially important given the emergence of TB strains resistant to almost all current TB drugs. “It’s an unprecedented experiment in history,” he says. “We’re generating a larger number of mutated bacteria, there’s no doubt about it.” Yet no one knows whether these strains are gaining new characteristics that allow them to mutate more quickly, he says, and Fortune’s work may help answer that important question.