Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Mechanism discovered by which body's cells encourage tuberculosis infection

11.12.2009
Finding how to block the pathway may lead to new therapies for TB and other disorders

Scientists have discovered a signaling pathway that tuberculosis bacteria use to coerce disease-fighting cells to switch allegiance and work on their behalf.

Epithelial cells line the airways and other surfaces to protect and defend the body. Tuberculosis bacteria co-opt these epithelial cells into helping create tubercles: the small, rounded masses characteristic of TB. The tubercles enable the bacteria to expand their numbers and spread to other locations.

By inciting parts of the immune system to go into overdrive, this same molecular signaling pathway may play other roles in inflammatory conditions such as arthritis and some forms of heart disease and cancer

"If we could keep this pathway from inciting the host immune system, we may be well on the way to finding innovative new therapies against TB, as well as other serious disorders," said the senior researcher on the study, Dr. Lalita Ramakrishnan, University of Washington (UW) associate professor of microbiology, medicine, and immunology. The results appear in the Dec. 10, 2009 express edition of Science.

Global health researchers are eager for new treatments for TB because many strains worldwide have become resistant to standard antimicrobials. Blocking a host pathway that the bacteria use would be an entirely different approach, Ramakrishnan explained, because it would keep the body from allowing the infection to take hold and be sustained, rather than a treatment aimed at killing the bacteria themselves. A host pathway blocker, if one becomes available, might also be quicker than current therapies, which take a long time to subdue the TB infection.

"Most diseases, such as high blood pressure and depression, are already being treated by blockers and inhibitors of host enzymes and pathways," Ramakrishnan noted, "Many of these turn down certain cell signals as part of their therapeutic action. We and some other researchers are now exploring the possibility of blocking or inhibiting molecular mechanisms in the body to prevent or treat infectious diseases as well. "

Earlier studies in the zebrafish by the Ramakrishnan lab demonstrated that TB tubercles were not, as previously thought, the way that the body walls off the bacteria to protect itself. Instead, these nodules (also called granulomas) are hubs for bacteria production and distribution. Uninfected macrophages – the body's frontline soldiers that can eat and destroy many bacteria – are recruited to the nodules, where they become TB-infected. However, the TB bacteria are able to grow in the macrophages, rather than being killed, likely by dampening the macrophages' defenses.

So by wooing more macrophages into the granuloma, the bacteria can use them to expand further. Some germ-laded macrophages then move to a new location, where they again attract more macrophages. New tubercles form and the scene is repeated.

Ramakrishnan and her research team have identified a molecular mechanism by which the mycobacteria that cause TB induce the body to form these production and distribution nodules. Researchers have long known that TB virulence is associated with a small protein the bacteria secrete, called ESAT-6.

Ramakrishan's group now has found that this secreted bacterial protein induces epithelial cells – the cells that make up membranous tissue covers inside the body – to produce an enzyme called MMP9. This enzyme has many functions including breaking down gelatin – a connective tissue protein -- into its components. In people, the presence of MMP9 is associated with increased susceptibility to infection and worse outcomes. The findings of this new study explain why this might be the case. MMP9 is also implicated in the development of several non-infectious inflammatory conditions, like arthritis, as well as heart disease and cancer.

Epithelial cells were once thought to be bystanders as tuberculosis took hold, according to the research group. However, their latest findings suggest that secretion of MMP9 by epithelial cells is amplified in the vicinity of a single TB infected macrophage. The activity of this enzyme draws in uninfected macrophages to join the infected macrophage to form and expand the granuloma.

"TB bacteria may have a two-prong strategy," said the first author of the Dec. 10 Science Express report, Dr. Hannah E. Volkman, who recently received her Ph.D. from the UW Molecular and Cellular Biology Program, "whereby the bacteria simultaneously suppress the macrophages inflammatory programs in order to create a hospitable niche inside them, while prodding epithelial cells to signal more macrophages to arrive and be unwitting participants in their home expansion project."

The researchers genetically "knocked out" MMP9 production in zebrafish embryos to see if that made them more resistant to TB. After TB infection, these embryos indeed had greater survival rates, fewer bacteria, and fewer granulomas than their normal, MMP9-producing siblings. This finding suggested that intercepting the production of MMP9 in epithelial cells should be further studied as a possible TB therapy.

"These novel findings," said Dr. William Parks, a UW professor of medicine and director of the UW Center for Lung Biology who was not part of this study, "point to new ways in which the body's resident cells can effect an inflammatory response and may have relevance beyond TB infection. The pathogen-to-epithelium-to-macrophage pathway they uncovered should provide several new avenues that could be targeted for intervention."

Co-authors of the article, "Tuberculous Granuloma Induction via Interaction of a Bacterial Secreted Protein with Host Epithelium," in addition to Volkman and Ramakrishnan, are Tamara C. Pozos, a former UW infectious disease fellow who is now on the faculty of Children's Hospital and Clinics of Minnesota; John Zheng, a UW medical student; J. Muse Davis, an M.D./Ph.D. student at Emory University; and John F. Rawls, assistant professor of cell and molecular physiology, University of North Carolina, Chapel Hill.

The study was funded by the Burroughs Wellcome Fund, Pew Scholars Program, National Institutes of Health, American Heart Association, Pediatrics Infectious Disease Society, Children's Health Research Center, and a National Defense Science and Engineering fellowship

Leila Gray | EurekAlert!
Further information:
http://www.washington.edu

More articles from Life Sciences:

nachricht Researchers identify potentially druggable mutant p53 proteins that promote cancer growth
09.12.2016 | Cold Spring Harbor Laboratory

nachricht Plant-based substance boosts eyelash growth
09.12.2016 | Fraunhofer-Institut für Angewandte Polymerforschung IAP

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Electron highway inside crystal

Physicists of the University of Würzburg have made an astonishing discovery in a specific type of topological insulators. The effect is due to the structure of the materials used. The researchers have now published their work in the journal Science.

Topological insulators are currently the hot topic in physics according to the newspaper Neue Zürcher Zeitung. Only a few weeks ago, their importance was...

Im Focus: Significantly more productivity in USP lasers

In recent years, lasers with ultrashort pulses (USP) down to the femtosecond range have become established on an industrial scale. They could advance some applications with the much-lauded “cold ablation” – if that meant they would then achieve more throughput. A new generation of process engineering that will address this issue in particular will be discussed at the “4th UKP Workshop – Ultrafast Laser Technology” in April 2017.

Even back in the 1990s, scientists were comparing materials processing with nanosecond, picosecond and femtosesecond pulses. The result was surprising:...

Im Focus: Shape matters when light meets atom

Mapping the interaction of a single atom with a single photon may inform design of quantum devices

Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...

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...

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

Researchers identify potentially druggable mutant p53 proteins that promote cancer growth

09.12.2016 | Life Sciences

Scientists produce a new roadmap for guiding development & conservation in the Amazon

09.12.2016 | Ecology, The Environment and Conservation

Satellites, airport visibility readings shed light on troops' exposure to air pollution

09.12.2016 | Health and Medicine

VideoLinks
B2B-VideoLinks
More VideoLinks >>>