To combat TB infection, early protection is essential

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Javier Rangel-Moreno and Shabaana Khader

Innate (green) and adaptive (red and white) immune cells in a lung surround and kill the bacteria that cause tuberculosis. Researchers from the Washington University School of Medicine in St. Louis and the Africa Health Research Institute have identified a main cell that coordinates the body's immune defenses in the first crucial days after infection. Strengthening the activity of such cells could help reduce millions of new infections that occur worldwide each year.

In the first few days after tuberculosis (TB) bacteria infect the body, a burst of immune cells is activated to fight the infection. Now, researchers have identified a main cell that coordinates the body's immune defenses in those crucial early days, according to a new study from the Washington University School of Medicine in St. Louis and the Africa Health Research Institute in KwaZulu-Natal, in South Africa.

The results, published in the journal Nature on June 5, suggest that strengthening the activity of these cells could help prevent deadly bacteria from taking hold in the lungs and reduce the tens of millions of new infections that occur every year.


Khader

"The immune response to tuberculosis bacteria depends on the early response of this cell, and this opens up a whole new avenue for tuberculosis control," said co-senior author Shabaana Abdul Khader, PhD, professor and head of interim of the Department of Molecular Microbiology at the School of Medicine. "Now we can start thinking about ways to target this cell to help the body fight bacteria before they have a chance to establish themselves."

According to the World Health Organization, in 2017, around 1.5 million people died of tuberculosis, making it the most lethal infectious disease in the world. While a vaccine is available, it only provides good protection against the most severe forms of the disease in young children and is less effective in older children and adults. Despite being widely used, the vaccine failed to stop the transmission of the disease and a quarter of the world's population is infected with tuberculosis bacteria.

"The positive results obtained from several recent vaccine studies make this an exciting time to work on the immunology of TB," said co-senior author Alasdair Leslie, PhD, a member of the Africa Health faculty Research Institute. "The more we can understand the interaction between the bacteria that cause tuberculosis and people, the more chance we have of building on these gains and defeating this deadly epidemic."

Vaccines are designed to alert the immune system to dangerous microbes by presenting bits of these microbes to adaptive immune cells. These cells remember what they saw and respond quickly if and when such microbes occur – ideally, before the microbes multiply and cause the disease. But in the case of tuberculosis, adaptive immunity alone, even if triggered by vaccination, may be too slow to protect people.

Khader, Leslie and colleagues – including co-authors Amanda Ardain, a graduate student in Leslie's lab, and Racquel Domingo-Gonzalez, PhD, and Shibali Das, PhD, both postdoctoral researchers in Khader's lab – studied animals and people to identify the immune system cells and proteins that defend the body from TB bacteria in the first few days after infection.

They found that cells known as innate group 3 lymphoid cells (ILC3) play a vital role in the first two weeks of infection. ILC3 cells belong to the innate branch of the immune system that detects and responds to foreign invaders in the body. Biologists have long believed that the innate immune system lacks memory for specific microbes, but recent studies suggest that some innate immune cells may have memory.

Experiments have shown that within five days of infection, ILC3 cells occur in the lungs, where they release chemical compounds that activate and attract other immune cells. Incoming cells include other innate immune cells – which are loaded with weapons that kill bacteria – as well as adaptive immune cells that direct and improve the killing potential of innate immune cells. Together, the immune cells surround the bacteria and destroy them.

In mice lacking ILC3 cells, immune responses are delayed and fail to take off. The activating chemical compounds are released later, the immune cells are slower to reach the lungs, the bacteria are not swallowed by the immune cells and, consequently, the mice are more sick and have more TB bacteria in the lungs. When the researchers gave ILC3 cells to mice that didn't have their ILC3 cells, they started the immune response, and the bacterial numbers never went up very high.

"These innate lymphoid cells seem to orchestrate all the first downstream immune responses – both innate and adaptive – that you need to control the infection," said Khader, who is also a professor of pathology and immunology.

In people and animals suffering from tuberculosis, ILC3 cells gathered in the lungs, especially in the immune structures that surrounded and killed bacteria. After the people were successfully treated with antibiotics, the ILC3 cells became more abundant in their bloodstream, suggesting that the cells were no longer needed in the lung to fight the infection.

Vaccine developers have largely ignored the innate immune system because it is believed to lack the ability to remember specific microbes. But recent studies have shown that innate immune cells may have memory or can be trained to be more effective, thus strengthening the body's innate immune defenses and providing wide-ranging protection. The tuberculosis vaccine – known as the BCG vaccine – was developed a century ago and designed to target the adaptive immune system. But now it is thought to work in part by training the innate immune system.

"Children who receive the BCG vaccine are protected not only against tuberculosis but also from various infectious diseases and cancer for a few years," Khader said. "They have lower rates of illness and death from all causes than children who have not been vaccinated. We would not like to replace the BCG vaccine, but we could find a compound that we can use to increase immunity in vaccinated children, when effects of BCG begin to fade ".

Khader's group began to examine a number of chemical compounds, looking for those that improve ILC3 activity and drive a stronger immune response in the first few days after infection.

"It's still an open question whether the ILCs in the lungs are trainable or have memory and how long the workout or memory will last," Khader said. "But if we can train them and get a population of these cells triggered and ready to go to the lung, this could be a way to make a vaccine more effective for tuberculosis."

Leslie added: "This study was an exceptional collaboration between scientists in South Africa and the United States and perfectly illustrates the power to bring together the skills on all continents to promote the science of tuberculosis."

/ Public release. View in full here.

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