Uncovering unique approaches to tuberculosis research 

3D illustration of a human's upper torso with the lungs visible. There is a close-up view of bacteria (Mycobacterium tuberculosis) inside the lungs.
When a person inhales the bacteria that causes Tuberculosis, the bacteria can settle and grow in the lungs. If not properly treated, tuberculosis can be fatal. Dr_Microbe – Adobe Stock

Tuberculosis (TB), a disease that primarily affects the lungs, is preventable and often curable. Still, more than 10 million people worldwide fall sick with the disease every year. 

World TB Day commemorates the day in 1882 that Dr. Robert Koch announced his discovery of the bacteria that causes TB. At the time, TB was colloquially known as “consumption” and had killed one out of seven people that had ever lived.  

Identifying the specific pathogen, along with many other advances in medicine since then, has made TB far less deadly than it historically was. It is still a leading infectious killer though, estimated to have caused 1.3 million deaths in 2022. The bacterium is also developing resistance to drugs commonly used against TB, making the disease increasingly difficult to treat. 

A more comprehensive look at people with tuberculosis 

The bacteria that causes tuberculosis seen through a microscope.
Labs perform an acid-fast stain to test whether a sample of blood, tissue or other body sample is infected with Mycobacterium tuberculosis. Here, the bacteria hold on to the dye, so the sample is positive for TB. DMH – Adobe Stock

In tuberculosis work, resources are mostly funneled into developing better diagnostic technology and finding new medicines. Far less thought is given to the barriers patients may face in accepting their diagnoses and completing treatment. 

“In what ways might the social circumstances of TB patients increase the risk of the bacteria multiplying within them? Or at risk of not completing therapy?” asked Marie Nancy Séraphin, an assistant professor at the University of Florida’s College of Medicine.  

To answer these questions, Séraphin, a member of the UF Emerging Pathogens Institute (EPI), studies the genetic diversity of Mycobacterium tuberculosis, the bacteria that causes TB in humans. The genetic makeup of M. tuberculosis populations changes during transmission and infection as the bacteria adapt to a new host. Different strains may rise to dominance depending on how successful they are at fighting a given patient’s immune system, and M. tuberculosis may also mutate once established inside the body. 

“The genetic data may tell us something about person-to-person transmission,” Séraphin said. “This could help public health officials prioritize interventions and stop community outbreaks.” 

Crucial forms of intervention include contact tracing to control transmission and support for those going through treatment. Because patients remain contagious during the early weeks, they must avoid others and stay home from work. This period of isolation poses social and financial strains, causing some patients to not complete treatment. But once someone begins treatment, their bacterial population drops sharply enough that they aren’t likely to transmit the disease to others. 

3D molecular model of Bedaquiline, a recently developed drug used to treat tuberculosis.
This 3D illustration shows the molecular structure of bedaquiline. This antibiotic is used as part of a treatment regimen for patients with multidrug-resistant tuberculosis. molekuul.be – Adobe Stock

“In tuberculosis, that is huge… If they weren’t able to go to work for six months while being treated, that would have a huge toll,” Séraphin said. “Some of the drugs may need to be taken with food, but I’ve seen patients who couldn’t take the drugs because they didn’t have food at home.” 

To get all this data, Séraphin partnered with the Korle Bu Teaching Hospital in Ghana to collect samples from recently diagnosed patients. She hopes that having more data points will help unlock secrets about which patients face the greatest risk of transmission and how likely a treatment plan is to succeed. Having a more complete picture of the bacterial diversity inside a patient also gives doctors a chance to make sure they’re prescribing an appropriate treatment.  

Despite ongoing transmission and treatment difficulties, Séraphin points to bedaquiline as a sign of progress. In 2012, bedaquiline became the first new drug that the U.S. Food and Drug Administration approved to treat TB in more than 40 years. In the fight against a disease with rampant drug resistance, having this additional tool offers new treatment options and renewed hope.  

Zooming out: What’s special about the genus tuberculosis belongs to? 

Luiz Pedro Sorio de Carvalho, a professor at the Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, is choosing to ask more fundamental questions about the bacteria itself. 

“We still don’t know what makes tuberculosis, tuberculosis,” said Carvalho, who is also an EPI member.  

Some bacteria, for example, cannot grow inside human cells. They are unable to take up nutrients and don’t have metabolic networks optimized for creating energy and sustaining themselves. 

But M. tuberculosis can, of course, grow inside human cells and cause disease. It belongs to the genus Mycobacterium – a diverse group. In addition to the bacteria that causes TB, other famous mycobacteria include those that cause leprosy, Buruli ulcer and Mycobacterium avium complex. In fact, Mycobacterium has more disease-causing bacteria than any other genus. 

At the same time, there are also several species of mycobacteria that live all around us in the soil and water without causing illness in most cases. The obvious question to ask, then, is how they become human pathogens. What changed? 

3D illustration of bacteria that cause leprosy.
Hansen’s disease, also known as leprosy, affects the skin and nerves. It is commonly caused by the bacteria Mycobacterium leprae, which belongs to the same genus as the bacteria that causes tuberculosis. freshidea – Adobe Stock.

“How did a bacterium that used to live in water or soil 100,000 years ago become adapted to human hosts?” Carvalho asked. Understanding what makes mycobacteria tick could be key to unlocking more effective treatment and prevention options. 

To answer these types of questions, Carvalho goes back to the beginning of mycobacteria. Bacteria in that genus have been evolving separately for long enough that researchers like Carvalho now have a range of genetic and biological differences to study.  

Carvalho looks at the evolutionary history of mycobacteria to identify which traits were present from the origin of the genus, as well as which emerged later. If a particular segment of DNA is present in every species of mycobacteria, that means it likely doesn’t play a role in adapting to a human host. But if a gene is only intermittently present, it may be worth investigating whether that trait makes a difference in a bacterial species’ ability to infect a human host. 

“By assembling an extensive library of mycobacteria, we dramatically increased biological diversity so we can ask these types of questions,” Carvalho said. 

This approach led to Carvalho’s lab’s discovery that, across the genus, sensitivity to antibiotics can vary by up to three orders of magnitude. They have also made key discoveries about how M. tuberculosis adapts its metabolism inside the human body. 

Supporting healthcare providers: who helps the helpers? 

A key difference between tuberculosis and other diseases is how extensive the treatment is. Doctors and patients need to think not only about administering the medicine, but also about protecting the medicine supply, making sure drug resistance doesn’t develop, and providing support over the extensive timeline of treatment. 

This is where the work of Michael Lauzardo, the EPI deputy director and an associate professor at the UF College of Medicine, is especially impactful. Lauzardo also serves as the director of the Southeastern National Tuberculosis Center (SNTC), one of four centers of excellence for tuberculosis control in the United States. 

A doctor and a patient sit at a desk and discuss the results of a chest X-ray.
A chest x-ray can help doctors see where TB bacteria are growing in the lungs. It can also help with diagnosing the disease, when combined with a blood, skin or sputum test. xreflex – Adobe Stock.

“TB is a big problem, but the battle is winnable,” Lauzardo said. “We still need some better medicines and better tools, but the biggest thing we’re still missing is the political will to truly eliminate that disease.” 

The SNTC, which is funded by the U.S. Centers for Disease Control and Prevention, focuses on helping the medical workforce stay up to speed on this dynamic battlefield, with the eventual goal of eradicating TB not only in the U.S., but also around the world. The center supports education and training programs throughout the southeastern U.S. and also offers consultations for healthcare providers working with patients with TB. 

But the biggest hurdle in eliminating tuberculosis, Lauzardo said, is political. Scientific advances have brought about better treatment regimens; however, simply having medicine available isn’t enough. There must also be economic development to provide resources to programs that prevent transmission and control the disease. 

“The number of tuberculosis cases in the United States has fallen over time. This is thanks to the investments that we put in public health,” Lauzardo said. 

Although Florida has the fourth highest number of TB cases in the country, this is largely because the state is so populous. Per 100,000 people, Florida sees approximately two infections – a middle of the road rate in the U.S. 

“We have a very strong tuberculosis control program here,” Lauzardo said. “We’re fortunate to have been able to work very closely with the Department of Health in the state of Florida.” 

Tuberculosis has been around for so long that it was even discovered as the cause of death in an Egyptian mummy around 2600 years old. But scientists like Séraphin, Carvalho and Lauzardo, do their work in hopes that the disease will one day be nothing more than a memory. 

“In the long term, I’m very encouraged by where we are in the fight. But there’s still a long way to go,” Lauzardo said. 

Written by: Jiayu Liang