Developing drug resistance may be a matter of diversity for tuberculosis

November 24, 2015 by Kelly April Tyrrell, University of Wisconsin-Madison
Developing drug resistance may be a matter of diversity for tuberculosis
The bacterial cells that infect a person with tuberculosis are highly diverse in individual patients with severe disease. The human body plays host to Mycobacterium tuberculosis cells that adapt readily to their environments and vary genetically. This diversity is especially prevalent in the genes that code for the bacterial cell envelope and may be important for host-pathogen interactions, including the development of drug resistance. Credit: Sue Medaris

To a microbe, the human body is a vast environment, full of resources and opportunities, dangers and threats. In the world of bacteria, it's thrive or fail to survive. Evolve or go extinct.

Caitlin Pepperell, professor of medicine and medical microbiology and immunology at the University of Wisconsin-Madison, wants to know more about microbes and their interactions with their human environments, particularly as more pathogens evolve resistance to the drugs we use to combat them.

In a new study recently published in PLoS Pathogens, Pepperell and colleagues at UW-Madison probed the bacteria that causes , Mycobacterium tuberculosis, to learn more about how individual bacterial cells change and adapt while in the .

"If you understand what evolutionary tricks the bug has, you are in a better position to tackle the emergence of resistance," says Pepperell, who is also an infectious disease physician. "What you want to do when you treat an infection is cause extinction, and the more you know about how the evolves, the smarter you can be about making it go extinct."

The researchers wanted to know: How diverse are the bacterial cells that reside within a single person? Where in the bacterial genetic code are the changes that lead to adaptation most extreme?

"Really, we set out to find patterns of diversity and what we could learn from them," Pepperell says.

To do this, they needed data in the form of the long strings of letters that make up the genetic code of individual tuberculosis bacterial cells harbored by patients with the disease. Tuberculosis bacteria primarily infect the lungs but can be found anywhere in the body, including the brain and kidneys.

The researchers found data collected from five patients in three previous studies, all of whom had severe disease and developed resistance to at least one common tuberculosis drug. The available data had been collected over time, as the patients underwent treatment and their disease progressed. Two ultimately died of tuberculosis, which was once the leading cause of death in the United States and is still often fatal, especially among people who develop drug resistant disease.

Developing drug resistance may be a matter of diversity for tuberculosis
Description: The outer cell envelope of the bacteria that causes tuberculosis, Mycobacterium tuberculosis, is rich in fatty molecules called lipids. This gives the bacterial cell an unusual waxy exterior. These lipids may also play a role in conferring drug resistance to the bacteria. Tuberculosis sickened more than 9 million people across the world in 2014 and half a million people were infected with bacteria resistant to common drugs to combat the illness. Credit: Sue Medaris

Since the researchers were interested in the evolution of the bacteria within each patient, they compared the genetic codes of the individual collected from each. They looked at how many letters within the code differed from one cell to the next within each patient and they looked at how much overall variation there was between each bacterial cell. From this, they derived a numerical way to describe the diversity of the bacterial populations found in each patient over time.

Most studies describe tuberculosis diversity by comparing one patient's tuberculosis to another, so that 50 patients might represent 50 different types of . Pepperell calls this the "sky-level view."

However, Pepperell says in their study they "zoomed in" and looked at the patterns of diversity of bacteria harbored by a single person with tuberculosis. Among individual patients with severe disease, they found vast diversity, even more so than between patients studied at sky-level. The findings mean there is more tuberculosis diversity within a single person with severe illness than there is tuberculosis diversity between people with the disease.

According to the World Health Organization, in 2014, 9.6 million people were sickened with tuberculosis, including 1 million children, and nearly 500,000 people developed multidrug-resistant disease. One third of the global population is infected with the tuberculosis bacteria, though only one in 10 of them will become sick with the disease in their lifetime.

The researchers also found that tuberculosis bacteria evolve substantially within their human hosts due to the pressures they face there, and that much of the genetic changes occur among the genes involved in making, regulating and transporting the cellular chemicals that form the fatty, waxy outer covering of the bacteria.

Other scientists studying everything from humans to mice have figured out that these genes interact with and manipulate the human immune system, says Pepperell. The researchers speculate the variability and redundancy in these cell envelope genes provide flexibility for the bacteria to rapidly adapt and become drug resistant.

This may present potential targets for new drugs in the future, or even vaccines to prevent tuberculosis infection.

With the data, Pepperell says they were also curious whether drug treatment reduced the diversity of the tuberculosis bacteria population in individual patients.

"We would hope, intuitively, that if you have a big, diverse population of bacteria and then you give treatment, the population of bacteria shrinks and there should be less diversity," Pepperell says. "We did not see that."

However, the team learned that as the severity of a person's illness progressed, the diversity of their bacteria increased. "What leads to someone dying of tuberculosis is the bacterial population getting completely out of control," Pepperell says.

New technology enabled the team to conduct the study this way, Pepperell says, and it's allowing other researchers to survey entire bacterial populations within the expansive environment that is the individual human body.

"When you think about it, it makes sense to do this, because the human body is where a microbe does its business," she says. It's the environment that impacts each person's bacterial residents most.

"If you only ever looked at one cell from this person and one cell from another person, you would be missing out on a lot of information about the environment the bacteria lives in, what it's doing, what it's responding to, what it has to cope with," Pepperell says. "I try to think like a mycobacterium. What would my life be like?"

Explore further: Tuberculosis genomes portray secrets of pathogen's success

More information: Mary B. O'Neill et al. Diversity of Mycobacterium tuberculosis across Evolutionary Scales, PLOS Pathogens (2015). DOI: 10.1371/journal.ppat.1005257

Related Stories

Tuberculosis genomes portray secrets of pathogen's success

August 21, 2013
By any measure, tuberculosis (TB) is a wildly successful pathogen. It infects as many as two billion people in every corner of the world, with a new infection of a human host estimated to occur every second.

Team discovers compounds with potential to treat persistent tuberculosis

November 17, 2015
Tuberculosis has been infecting humans for several millennia, making it one of the most horribly successful diseases in history. Today, it is still a major killer, responsible for some 1.5 million deaths each year.

Zombie bacteria in tuberculosis

January 26, 2015
"Living-dead" bacteria exist in limbo: biologically active but not proliferating. Buried in this zombie state, disease-causing bacteria could come back from the dead to re-infect patients. Researchers at EPFL have produced ...

TB lung infection causes changes in the diversity of gut bacteria in mice

May 13, 2014
Johns Hopkins researchers have found evidence in mice that a tuberculosis (TB) infection in the lungs triggers immune system signaling to the gut that temporarily decreases the diversity of bacteria in that part of the digestive ...

Bacteria evolve differences within the lungs of patients with cystic fibrosis

August 20, 2015
Treatments for the same opportunistic bacteria found in cystic fibrosis patients can work in one area in the lung and be less effective in others. The reason, reported August 20 in Cell Host & Microbe, is that bacteria become ...

FDA approves first new tuberculosis in 40 years

December 31, 2012
The Food and Drug Administration says it has approved a Johnson & Johnson tuberculosis drug that is the first new medicine to fight the deadly infection in more than four decades.

Recommended for you

Experimental vaccine shows promise in preventing TB

September 25, 2018
(HealthDay)—Tuberculosis remains the most lethal of infectious diseases worldwide, killing more than 1.6 million people a year. But researchers say a new vaccine might prevent half of full-blown illnesses in infected people ...

Researchers seek vaccine for 'traveler's diarrhea'

September 25, 2018
Every year, millions of people have vacations and business trips ruined when they succumb to "traveler's diarrhea" during their journeys. A major cause of traveler's diarrhea is bacteria called Enterotoxigenic E. coli, or ...

Many doctors in India miss TB signs: study

September 25, 2018
Many private sector doctors in India miss the signs of tuberculosis and therefore provide patients inadequate treatment, according to a new study published Tuesday involving people hired to act out the symptoms.

New way of determining treatment for staph infections cuts antibiotic use

September 25, 2018
Using a clinical checklist to identify eligible patients, doctors were able to shorten the antibiotic duration for patients with uncomplicated staphylococcal bloodstream infections by nearly two days, Duke Health researchers ...

Breakthrough in designing a better Salmonella vaccine

September 24, 2018
UC Davis researchers announce in the Proceedings of the National Academy of Sciences this week a breakthrough in understanding which cells afford optimal protection against Salmonella infection—a critical step in developing ...

Antifungal agent found to be possible treatment for porphyria

September 24, 2018
A large team of researchers from Spain, France and the U.S. has found that a common antifungal agent might be useful as a treatment for a rare type of porphyria. In their paper published in the journal Science Translational ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.