Tuberculosis bacteria can 'play dead' to survive immune response

The vaccine protects more than 100 million infants each year from severe forms of tuberculosis (TB), including the deadly swelling of the brain that can develop in infants. But the same vaccine does not prevent the more common form of TB in adults, which attacks the lungs. This allows the disease to remain the world's deadliest infectious disease, killing 1.25 million people a year.

The current TB vaccine produces a powerful immune response, according to most studies. But standard measures of immunity don’t predict protection in adults. So scientists at Tufts University’s Cummings School of Veterinary Medicine, the University of Utah, the Harvard T.H. Chan School of Public Health, and Texas A&M University took a new approach — they studied how the TB bacterium evades the immune system that’s primed to destroy it.

Their genetic study in mice, recently published in npj Vaccines, showed that TB bacteria can essentially "play dead" to survive the immune response.

Tuberculosis is also known by its historical name, consumption, a term that reflects the slow, debilitating, and often fatal progression of the disease.

“There is an urgent need for better prevention because treatment alone will not stop the spread of TB,” says Amanda Martino, MD, MPH, PhD, associate professor at the Cummings School of Veterinary Medicine and co-author of the study. “When TB drugs became available more than 60 years ago, cases dropped dramatically around the world. But TB has returned with the HIV epidemic and is becoming increasingly resistant to traditional antibiotics. Now, there are only a few new drugs available to treat resistant TB, making it much more difficult to cure.”

Unlike other respiratory diseases such as influenza or COVID-19, which are caused by viruses and require constant vaccine updates due to their frequent mutations, TB is caused by a very genetically stable bacterium, Mycobacterium tuberculosis. In theory, this means that the disease should be easy to prevent with a vaccine.

In their study, the team used a technique called transposon insertion sequencing (TnSeq) to determine which genes the bacteria needed to survive in four groups of mice.

• The first group was vaccinated with an existing vaccine (developed over 100 years ago from a strain of TB in cows).
• The second received an experimental vaccine based on a human strain of TB, which preclinical studies have shown to induce a stronger immune response.
• The third group had previously been infected with TB and then treated with antibiotics.
• The fourth group (control) had never been exposed to the vaccine or infection.

The scientists expected to find key genes that the bacteria use to survive in vaccinated hosts, and indeed they found several potential targets for future vaccines. But the biggest surprise was the genes that the bacteria did not need after vaccination or infection.

“We were particularly surprised that certain genes that are normally important for the bacteria to grow quickly and cause serious TB infection were not as necessary when the bacteria infect a body with a pre-existing immune response – whether from vaccination or a previous infection,” Martino said.

Instead, the researchers found that TB bacteria switch their strategy, relying on other genes that help them cope with stress and "freeze" in an unfavorable environment.

“We suspect that the bacteria are kind of ‘laying low,’ keeping quiet until the immune response is weakened — whether by vaccine efficacy, HIV, or other factors,” explains Allison Carey, an associate professor at the University of Utah and co-author of the study.

These findings could help scientists create drugs that can be used alongside vaccines to help the immune system "smoke out" TB from where it hides.

The team also found that different vaccines, or the way they are given, alter which genes TB needs to survive. This shows that different vaccines put different pressures on the bacteria, and opens the way to new, more effective vaccine-booster combinations.

“This bacterium is incredibly well adapted to survive in the immune system,” says Martino. “It has been infecting people since ancient Egypt. More research is needed to finally outsmart TB and get this global emergency under control.”