September 11, 2013

Cornell Professor Seeks Cure for Tuberculosis

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By REEM KHONDAKAR

According to the World Health Organization, about two million tuberculosis-associated deaths occur annually worldwide. Prof. David Russell, microbiology and immunology, is investigating how tuberculosis lives inside the human cell meant to kill it and working to find a treatment to the increasingly drug-resistant disease.

Known throughout history as consumption, white plague and Pott’s disease, tuberculosis is one of the oldest diseases that has plagued mankind. According to Russell, since the first human migration out of Africa approximately 60,000 years ago, tuberculosis has followed the poorest, most crowded and most immune-compromised populations on earth.

Tuberculosis is caused by mycobaterium tuberculosis, a pathogen that easily spreads from person to person by its ability to remain airborne for hours in droplets called nuclei. Inhalation of these droplet nuclei can cause the illness, which generally affects the lungs. The pathogens infect macrophage cells, immune cells that clean up debris from dead tissues and which engulf and usually destroy bacteria. However, tuberculosis has evolved to persist inside the macrophage environment; as a result, the immune cell meant to protect us from tuberculosis actually harbors the bacteria.

“There’s strong evolutionary pressure in both directions in terms of developing mechanisms to clear bacteria and bacteria developing mechanisms to avoid clearance,” Russell said. “I think the two organisms are very finely evolved and adapted to one another, and that’s why we have this persistent infection.”

Macrophages are known for picking up many complex carbohydrates such as cholesterol, which, coincidentally, the mycobacterium can feed on. Tuberculosis can also turn off growth in response to environmental stressors. By turning off growth, the bacteria have the advantage of persisting in a chronic, non-replicating state.

There are two forms of tuberculosis: latent and active. In both forms, the bacteria are engulfed by macrophages, which envelope the bacteria in a process called phagocytosis. This macrophage, which is now considered infected by the bacteria, recruits other immune cells to the site. This accumulation of cells is called a granuloma, which is “the defining pathology of tuberculosis,” according to Russell.

Although the granuloma cannot destroy the bacteria, it does contain it.

“The granuloma is the product of the bacterium and the host,” Russell said. “For the bacterium, it allows the bacteria to persist. For the host, it walls off the infection and prevents spread of the infection.”

One-third of the world’s population is afflicted with tuberculosis, Russell said. However, in that group, only five to 15 percent develop the active disease. For the majority of people afflicted, tuberculosis is dormant.

“I think its because the bacteria is highly evolved and we’re highly evolved,” Russell said. “For the majority of individuals, our immune system does a very good job.”

Yet for people who do not have a working immune system, the story is quite different. Immune-compromised individuals have a higher chance of developing tuberculosis. If the granulomas rupture, the bacteria are free to spread throughout the airways, thus causing the active form of the disease.

“If you have HIV, you can’t make granulomas, and you can’t contain the infection,” Russell said.

Although a treatment for tuberculosis exists, it is fraught with complications. Current treatment involves a combination of three to four front-line drugs and can take between three to nine months to complete.

According to Russell, because the long-term, difficult treatment carries a higher risk of non-compliance, there is a serious danger of selection for drug-resistant bacteria. Patients who quit treatment too early allow the bacteria to acquire mutations for resistance.

“It’s a perfect recipe for selection of drug-resistant strains,” Russell said. “We see drug-resistant strains being selected for in multiple geographic locations across the world. It’s not just a one-off thing.”

According to the WHO, in 2011 alone there were over 300,000 cases of multi-drug-resistant tuberculosis. New drugs have the potential to not only avoid the growing problem of multi-drug-resistance, but also make therapy much shorter and less taxing.

Russell’s lab aims to find better treatment for tuberculosis. He and Brian VanderVen, a research scientist in microbiology and immunology, is currently working with Vertex Pharmaceuticals, a drug-company based in Boston, to screen organic compounds that can limit tuberculosis growth in the macrophage environment.

From Vertex’s library of about 340,000 compounds, the lab has homed in on about 300 potential “hits” that could work effectively against tuberculosis inside the macrophage. To find these hits, researchers transform the tuberculosis pathogen so that it will express a red fluorescent protein. Then, they create mixtures of macrophages, tuberculosis, and the compound in question.

After incubating the mixtures for six days, they measure the amount of fluorescence. Low fluorescence mixtures are marked as a potential hit.

Russell looks for drugs that are at least 70 percent as effective against the bacteria as are established drugs. Through their work, researchers in Russell’s lab found that studying tuberculosis alone was not enough.

The relationship between the human macrophage and intracellular pathogens was not exclusive to the mycobacterium.

“We realized that if we’re interested in tuberculosis in Africa we could not ignore HIV. We had to study HIV in parallel,” Russell said.

The Russell Lab has two ongoing drug discovery programs in Malawi. One is for anti-tuberculosis agents, and the other is for a more recent project: anti-inflammatory agents against cerebral malaria, a main cause of pediatric malarial deaths in Sub-Saharan Africa.

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