NEW ORLEANS – University of Michigan microbiologists have created a virtual model of the human immune system that runs "in silico" to study what happens inside the lungs after people inhale Mycobacterium tuberculosis, the bacterium that causes TB.
The computer model is helping scientists learn more about this ancient pathogen, and why some people are able to fight off the infection, while others get sick. U-M scientists believe the answer could be hidden inside structures called granulomas, which immune cells build to surround and contain invading M. tuberculosis bacteria.
"Granulomas are the hallmark of tuberculosis," says Denise Kirschner Ph.D., an associate professor of microbiology and immunology in the U-M Medical School. "It's the immune system's fail-safe response to infection. If the immune system can't clear the pathogen, it gets out the masonry and walls it off."
Kirschner presented research results and an analysis of time-lapse computer animations showing granuloma formation at a May 26 seminar during the American Society for Microbiology's annual meeting held here this week.
"M. tuberculosis has been living with people for at least 4,000 years," says Kirschner. "Because the bug has had all those years to get to know us so well, it has evolved several effective ways to circumvent the immune system's ability to detect and kill invading pathogens. Scientific knowledge of how the immune system interacts with M. tuberculosis is slowly improving, but we are far from prevention or an effective vaccine. It's important to understand TB, because the disease is a serious and growing public health problem."
According to Kirschner, approximately 2 billion people worldwide are infected with M. tuberculosis, and the disease kills about 3 million people every year. In the early stages of infection, tuberculosis can be treated with powerful antibiotics, but there is no cure. And multi-drug-resistant strains, which are essentially untreatable, are becoming more common.
The immune system's immediate response to the presence of M. tuberculosis in the lungs is to surround the bacteria with immune cells called macrophages, which signal other immune cells to join them for a group assault on the invading bacteria, Kirschner says. About 90 percent of the time, these multi-cellular structures called granulomas are enough to stop the bacteria from spreading. Although the individual will always be infected with TB bacteria, the disease will remain in a latent phase and produce no symptoms, unless it flares up again later in life.
Between 5 percent to 10 percent of the time, however, granulomas fail to contain the bacteria. Unless the disease is diagnosed and treated, TB bacteria will continue to spread through the lungs, eventually producing severe respiratory symptoms and death.
Since granulomas are the key counter-offensive in the war between the human host and M. tuberculosis, Kirschner and U-M post-doctoral fellows Jose Segovia-Juarez, Ph.D., and Suman Ganguli, Ph.D., programmed their computer model with experimental data from studies - directed by University of Pittsburgh collaborator Joanne Flynn, Ph.D. - of research animals infected with TB. They then created time-lapse animations demonstrating what happens as a granuloma forms after initial infection with the bacteria.
When they analyzed the results of the computer simulation, Kirschner and her research team found new clues to the immune system's containment process:
- Granulomas that were unable to contain TB bacteria were packed with inactive macrophages, making it impossible for T cells to get inside the granuloma and properly signal the macrophages to attack and kill M. tuberculosis bacteria. - The arrival time, number and location of "educated" T cells, which had been primed by the immune system to signal macrophages to attack M. tuberculosis, were crucial to the success of the immune response.
- The slow reproduction rate of M. tuberculosis bacteria, which doubles about every two days, helps the bacteria survive undetected inside macrophages for long periods of time.
Mathematical models are a valuable addition to experimental research, because they make it possible to study complex biological systems with many variables in ways that would be impossible in humans or research animals.
"Here we used a new approach called agent-based modeling, which allowed us to track the individual behavior of specific cells in the system and how they contributed to the collective outcome," Kirschner says. "This is one of first applications of this method in studies of infectious diseases within the host."
Kirschner's research is funded by the National Heart, Lung and Blood Institute of the National Institutes of Health.
Note: Animations of granuloma formation described in this story can be viewed in AVI format on the Web at http://malthus.micro.med.umich.edu/lab/abm/movies/. The first version (clearance.avi) shows what happens to the granuloma when the immune system is able to destroy the bacteria. The second version (containment.avi) shows granuloma formation when infection is contained. The third version (dissemination.avi) shows what happens to the granuloma when the infection is not contained.
Cells are color coded as follows: Inactive macrophages (green), activated macrophages (blue), infected macrophages (orange), chronically infected macrophages (red), T cells (pink), necrotic tissue (brown) and extracellular bacteria (yellow).
Additional Contact:
Kara Gavin, kegavin@umich.edu, 734-764-2220