Sarah Fortune, assistant professor of immunology and infectious diseases at Harvard School of Public Health, received her MD from Columbia University in 1996 and experienced New York City at a time when HIV was highly prevalent. Concurrent with this HIV/AIDS epidemic were tuberculosis (TB) outbreaks among the HIV-infected population. This “co-infection epidemic” presented a serious public health problem. The medical and research communities had made tremendous progress in treating HIV/AIDS, but controlling and treating TB had not fared so well. Dr. Fortune knew something had to be done, and was determined to play a role in doing it.

In a paper titled, “Use of whole genome sequencing to estimate the mutation rate of Mycobacterium tuberculosis during latent infection,” published in the May 2011 issue of Nature Genetics, Fortune and colleagues explored the ability of TB to mutate and become drug resistant, and as a result have discovered aspects of the disease that seriously call into question current approaches to treatment and care.

More than one-third of the world’s population is infected with the bacterium that causes TB, and roughly two million people die from the disease each year. It is most prevalent in Sub-Saharan Africa, where in some places about one in 100 people have an active form of TB. This statistic is especially concerning given the high rate of HIV in Africa, which makes TB easier to contract. TB is also highly rampant in China and India, where population density contributes to its spread.

At HSPH, Sarah Fortune’s lab focuses on M. tuberculosis (Mtb), the bacterium responsible for TB, in particular, how its ability to mutate contributes to drug resistance.

For her recent paper, Fortune and colleagues explored how Mtb mutates and becomes drug resistant during different stages of the disease. In active TB, the disease state that produces symptoms and occurs in 10 percent of those infected, the bacteria are thought to be continuously growing. In latent TB, in which the host is largely asymptomatic, the bacteria are thought to be inert. While 10 percent of those with latent TB will eventually develop an active form of the disease, the rest will not.

The common thinking within the scientific community is that during active TB, the bacterium mutates at a high rate, while in latent TB the bacterium is stagnant and does not mutate at all. For this reason, active TB is aggressively treated with four different drugs. Latent TB, on the other hand, is treated with only one drug, called isoniazid, considered to be sufficient given the widespread belief that during latency, Mtb does not mutate.

Fortune’s findings challenge this.

In a non-human primate host, she and her team found that in active and latent TB, the bacterium acquires mutations at exactly the same rate, and that this rate is slightly higher than that measured for active TB in the lab. Fortune believes immune pressure might be driving mutation, especially in latent TB. “The bacteria are in a toxic environment, which causes the host’s immune system to bombard the bacteria with assaults,” Fortune says. “This creates a dangerous double-edged sword.” The immune system is trying to destroy the bacteria and protect the host, but this also causes the surviving bacteria to mutate and acquire drug resistances.

The clinical implications of this finding are especially relevant since The World Health Organization (WHO) has recently recommended that isoniazid preventive therapy (IPT) be rolled out to HIV-infected individuals in places where latent TB is highly prevalent. “We are fixated on treating latent TB with just one drug,” says Fortune. “But it might make sense to reconsider a two-drug regimen in treating latency, especially in the setting of HIV where patients are at high-risk of developing the disease.” Fortune also believes the methods of screening for drug resistance in TB-infected populations need to be more sophisticated. This is particularly important in places like Africa, where TB is very common, but resources for effective screening for drug resistances are scarce.

In Boston, the chances of contracting TB are four in 100,000, about 250 times lower than in Sub-Saharan Africa. While it is still a serious disease and difficult to treat, the United States has the money and resources in place to ensure TB doesn’t become a serious public health problem. The U.S. has made significant progress in controlling TB, but the same cannot be said for other places around the world.

“It’s scary,” admits Fortune. “In some places, strains of TB have developed resistance to pretty much all of the drugs we have. It’s not like TB is going to sweep across the United States, but there is an inexorable spread of drug resistant TB in other places that we can’t ignore.”