Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Fighting TB might be a matter of 'flipping a switch' in immune response

24.06.2009
Scientists are focusing on a new concept in fighting airborne pathogens by manipulating what is called the “switching time,” the point at which a highly regulated immune response gives way to powerful cells that specialize in fighting a specific invading bug.

In the case of tuberculosis, Ohio State University researchers are using mathematical modeling to determine whether a change to the natural switching time would result in a more effective immune response. They also are analyzing which parts of the immune response are most important to striking a balance between properly timing the switch and completing the task at hand – killing the microbe.

The complex modeling takes into account the huge assortment of cells and molecules at work in the human immune response to Mycobacterium tuberculosis, the microbe that causes TB. The response to all airborne pathogens is particularly complicated because it takes place in the highly protective environment of the lung. Human lungs are programmed to minimize immune responses as a way to avoid inflammation, which could interfere with breathing.

The modeling suggests that the average switching time occurs about 50 days after tuberculosis invades the lung, which roughly coincides with clinical expectations that a skin test will turn up positive for TB between four and eight weeks after infection.

By that time, bacteria have settled in and are harder to kill, even with the more robust immune response. Because TB is highly evolved and adapted to the human host, the launch of the stronger immune response goes unnoticed in about 90 percent of infections.

With less adapted but virulent pathogens, on the other hand, an individual becomes acutely ill, and sometimes dies, when the switching time occurs. As the immune response kicks into high gear, toxic infection-fighting warrior cells cause what could be considered collateral damage by harming lung tissue at the same time that they kill the invading bugs.

The researchers say mathematical models that predict relationships and interactions in the immune response could guide planning for therapies that would be designed to either accelerate or slow the switching time, depending on the pathogen.

“A great problem in developing drugs and vaccines against airborne pathogens is this apparent bottleneck in the immune response and the inability to quickly and effectively eradicate microbes in the lung environment,” said Larry Schlesinger, professor of internal medicine and director of the division of infectious diseases at Ohio State and a senior author of the study. “Understanding that bottleneck is an important part of this paper, and brings new insight into how to override the problem with tuberculosis and other pathogens.”

The research is scheduled to appear in the online early edition of the Proceedings of the National Academy of Sciences.

About 2 billion people worldwide are thought to be infected with TB. People who are infected can harbor the bacterium without symptoms for decades, but an estimated one in 10 will develop active disease characterized by a chronic cough and chest pain. Both active and latent infections are treated with a combination of antibiotics that patients take for at least six months.

In the event of infection, two immune responses occur: The innate immune response begins a fight against any pathogen. The acquired immune response follows, with components designed to attack the specific pathogen causing the infection. When that change occurs is referred to as the switching time.

At the point of infection in the lung, TB bacteria are absorbed by what are called alternatively activated macrophages. These macrophages activate specific molecules that make pieces of the bacteria visible to infection-fighting T cells, a process that triggers an eventual T-cell response and the recruitment of classically activated macrophages, those that are more effective at killing bacteria.

The mathematical modeling in this study simulates the entire cascade of events in the immune response to TB, setting the stage for testing what the outcome would be if changes were made along the way – for example, if a drug were developed to artificially inhibit or activate part of the process.

In this research, the scientists sought to determine what it would take to shorten the switching time and reduce the number of bacteria in the lung.

Two cytokines, interferon gamma and tumor necrosis factor alpha, are known participants in the conversion from one type of immune response to the other. Cytokines are proteins mobilized when the body is injured or has an infection, and often cause inflammation in their repair efforts.

Many previous studies testing interferon gamma’s potential as a TB therapy have suggested that the protein is effective in the fight, but isn’t effective enough on its own to treat the infection. The mathematical modeling simulating such a treatment reinforced these findings.

The model showed that early introduction of interferon gamma during the immune response would shorten the switching time and reduce the bacterial load, but would not completely clear bacteria from the lung after 100 days – a population referred to as the residual bacterial load. The researchers speculate that manually introducing one cytokine is not enough to optimize the signals needed to activate certain macrophages.

The findings suggest that interferon gamma might be one component of a cocktail approach to new TB therapies, the researchers said.

There would be a benefit to reducing that residual load of bacteria, Schlesinger noted. TB treatments take so long and currently require a cocktail of antibiotics specifically to address the long-term persistent bacteria in the lung and other parts of the body.

“If we could shorten the treatment for TB, that would be very powerful in breaking the transmission cycle,” said Schlesinger, also director of Ohio State’s Center for Microbial Interface Biology.

The precision of the modeling allows the researchers to simulate outcomes resulting from multiple tweaks to the values assigned to the various immune response activities.

“It’s like turning the knobs up and down on an equalizer, only in this case to figure out when the immune response and different mediators of that response are at the right levels to do their jobs – without blowing the speakers, so to speak,” said Judy Day, a postdoctoral researcher in Ohio State’s Mathematical Biosciences Institute and lead author of the study.

The researchers conducted a number of sensitivity tests to check the validity of the models. The models use what are considered ordinary differential equations, but finding the values to plug into those equations required an exhaustive search of previous research on tuberculosis.

“To pin down quantitatively what the effect of A is on B and C, we had to search the literature to find evidence of these parameters. When we didn’t find them, we had to make educated guesses and then subject them to sensitivity analysis,” said Avner Friedman, a senior author of the paper and Distinguished University Professor of mathematical and physical sciences at Ohio State.

Friedman, who was the founding director of the Mathematical Biosciences Institute, predicts this line of mathematical modeling of the immune response has paved the way for new research into combination therapies against a variety of pathogens.

“Switching time is a new concept. We will be talking about switching time in a few years about this disease, or that disease,” he said.

This research was supported by grants from the National Science Foundation and the National Institutes of Health.

Larry Schlesinger | EurekAlert!
Further information:
http://www.osumc.edu

More articles from Life Sciences:

nachricht Multi-institutional collaboration uncovers how molecular machines assemble
02.12.2016 | Salk Institute

nachricht Fertilized egg cells trigger and monitor loss of sperm’s epigenetic memory
02.12.2016 | IMBA - Institut für Molekulare Biotechnologie der Österreichischen Akademie der Wissenschaften GmbH

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Novel silicon etching technique crafts 3-D gradient refractive index micro-optics

A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.

Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...

Im Focus: Quantum Particles Form Droplets

In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.

“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...

Im Focus: MADMAX: Max Planck Institute for Physics takes up axion research

The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.

The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...

Im Focus: Molecules change shape when wet

Broadband rotational spectroscopy unravels structural reshaping of isolated molecules in the gas phase to accommodate water

In two recent publications in the Journal of Chemical Physics and in the Journal of Physical Chemistry Letters, researchers around Melanie Schnell from the Max...

Im Focus: Fraunhofer ISE Develops Highly Compact, High Frequency DC/DC Converter for Aviation

The efficiency of power electronic systems is not solely dependent on electrical efficiency but also on weight, for example, in mobile systems. When the weight of relevant components and devices in airplanes, for instance, is reduced, fuel savings can be achieved and correspondingly greenhouse gas emissions decreased. New materials and components based on gallium nitride (GaN) can help to reduce weight and increase the efficiency. With these new materials, power electronic switches can be operated at higher switching frequency, resulting in higher power density and lower material costs.

Researchers at the Fraunhofer Institute for Solar Energy Systems ISE together with partners have investigated how these materials can be used to make power...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ICTM Conference 2017: Production technology for turbomachine manufacturing of the future

16.11.2016 | Event News

Innovation Day Laser Technology – Laser Additive Manufacturing

01.11.2016 | Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

 
Latest News

UTSA study describes new minimally invasive device to treat cancer and other illnesses

02.12.2016 | Medical Engineering

Plasma-zapping process could yield trans fat-free soybean oil product

02.12.2016 | Agricultural and Forestry Science

What do Netflix, Google and planetary systems have in common?

02.12.2016 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>