New Approach Could Help Develop More Effective Vaccine – ScienceDaily

The results, published on June 5 in the journal Nature, suggest that enhancing the activity of these cells could help prevent deadly bacteria from gaining a foothold in the lungs and reducing the tens of millions of new infections that occur each year.

"The immune response to the TB bacteria depends on the early response of this cell, which opens a new pathway for TB control," said lead co-author Shabaana Abdul Khader, PhD, professor and interim chief of the department. of Molecular Microbiology at the Faculty of Medicine. "We can now start thinking of ways to target this cell to help the body fight bacteria before they have the chance to establish themselves."

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

"Positive results from several recent vaccine trials make this an exciting time to work in TB immunology," said co-lead author Alasdair Leslie, PhD, a faculty member of the Institute for Research on Disease. health in Africa. "The more we can understand the interaction between the bacteria that cause TB and the people, the more likely we are to take advantage of these gains and defeat this deadly epidemic."

Vaccines are designed to warn the immune system of dangerous microbes by presenting fragments of these microbes to adaptive immune cells. These cells remember what they have seen and react quickly if such microbes appear, ideally, before they multiply and cause the disease. But in the case of tuberculosis, adaptive immunity alone, even when it is vaccinated, may be too slow to protect people.

Khader, Leslie, and colleagues – including co-first authors Leslie Graves graduate student Amanda Ardain, and Dr. Racquel Domingo-Gonzalez, Ph.D., and Shibali Das, Ph.D., both postdoctoral researchers in the lab. Khader – have studied animals and people to identify immune cells and proteins that defend the body against tuberculosis bacteria in the first days after infection.

They found that cells known as Group 3 Inborn Lymphoid Cells (ILC3) play a critical role during 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 appear in the lungs, where they release chemical compounds that activate and attract other immune cells. The cells that arrive include other innate immune cells – which are loaded with bacteria-destroying weapons – as well as adaptive immune cells that direct and reinforce the destructive potential of innate immune cells. Together, the immune cells surround the bacteria and destroy them.

In mice lacking ILC3 cells, the immune response is delayed and has difficulty in taking off. The activating chemical compounds are released later, the immune cells arrive more slowly in the lungs, the bacteria are not engulfed by the immune cells and, therefore, the mice are sicker and have more TB bacteria in the lungs. When the researchers administered ILC3 cells to mice lacking their own ILC3 cells, the immune response was triggered and the number of bacteria never went up very high.

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

In people and animals with tuberculosis, ILC3 cells have gathered in the lungs, particularly in the immune structures surrounding and destroying bacteria. Once people were successfully treated with antibiotics, ILC3 cells became more numerous in their bloodstream, suggesting that cells were no longer needed in the lung to fight the infection .

Vaccine designers have largely ignored the innate immune system because it is thought that he is unable to remember specific microbes. But recent studies have shown that innate immune cells can have memory or be trained to be more effective, strengthening the innate immune defenses of the body and offering extended protection. The TB vaccine – called BCG vaccine – was developed a century ago and was designed to target the adaptive immune system. But now it is thought to work in part by forming the innate immune system.

"Children who receive the BCG vaccine are protected not only against TB, but also against many infectious diseases and cancer for a few years," Khader said. "Disease and all-cause mortality rates are lower than those of unvaccinated children, we would not want to replace the BCG vaccine, but we may be able to find a compound that we can use to enhance the immunity of vaccinated children, when the effects of BCG begin to fade ".

Khader's group has begun to screen for a set of chemical compounds, looking for those that enhance the activity of ILC3 and strengthen the immune response in the early days following infection.

"The question of whether the CILs in the lung can be trained or have a memory and how long the training or memory will remain an open question," Khader said. "But if we can train them and prepare a population of these cells and it is ready to enter the lungs, this could be a way to make a more effective vaccine against tuberculosis."

Leslie added, "This study is an exceptional collaboration between scientists from South Africa and the United States, and perfectly illustrates the power of bringing together expertise from all continents to advance the science of tuberculosis."