Navigation Links
Mechanism discovered by which body's cells encourage tuberculosis infection
Date:12/10/2009

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."


'/>"/>

Contact: Leila Gray
leilag@u.washington.edu
206-685-0381
University of Washington
Source:Eurekalert  

Related medicine news :

1. Researchers uncover novel mechanism that balances the sizes of functional areas in the brain
2. UCSD study reveals the regulatory mechanism of key enzyme
3. Ancient mechanism for coping with stresses also gives cancer a boost
4. UCSD study reveals the regulatory mechanism of key enzyme
5. Researchers at IRB Barcelona discover one of the mechanisms that prevents the spread of colon cancer
6. Researchers chart the genetic mechanisms behind the genesis of fat cells
7. Research suggests mechanism for acne drugs link to depression
8. St. Jude finds mechanism for faulty protein disposal
9. St. Jude Finds Mechanism for Faulty Protein Disposal
10. Study suggests nicotine addiction might be controlled by influencing brain mechanisms
11. Quality control mechanism tags defective sperm cells inside the body
Post Your Comments:
*Name:
*Comment:
*Email:
Related Image:
Mechanism discovered by which body's cells encourage tuberculosis infection
(Date:2/24/2017)... ... 2017 , ... With ProGlass Prism users now have the ability to simulate ... over position, rotation, distortion, edge softness, edge blur, chromatic aberration, individual glass position offset, ... ProGlass Prism users are given the tools and effects to generate a fractal ...
(Date:2/24/2017)... ... February 24, 2017 , ... The International Association of Eating ... Me Beyond What You See” body image mannequin art competition. Selected from 15 submissions ... and the winner revealed at the 31st annual iaedp Symposium, March 22 – 26 ...
(Date:2/24/2017)... ... February 24, 2017 , ... ... specializes in thought leadership , media relations, social media, content marketing and ... will be powered through Act-On, an intuitive marketing automation platform. , Rosica will ...
(Date:2/23/2017)... ... February 23, 2017 , ... Thinksport, the most award-winning sunscreen ... Fondo of Marin. For the second year in a row, cyclists will stay ... “We are thrilled to provide our safe, non-toxic sunscreen to over 2,000 cycling ...
(Date:2/23/2017)... , ... February 23, 2017 , ... ... devoted exclusively to funding innovative lymphoma research and serving the lymphoma community through ... return to the La Gorce Country Club in Miami Beach to host its ...
Breaking Medicine News(10 mins):
(Date:2/23/2017)... Feb. 23, 2017 Regulus Therapeutics Inc ... and development of innovative medicines targeting microRNAs, today announced ... financial results on Thursday, March 2, 2017 after the ... call and webcast on March 2, 2017 at 5:00 ... year 2016 financial results and provide a general business ...
(Date:2/23/2017)... ... Markets has announced the addition of the "Global Antifungal Drugs Market ... offering. The Global Antifungal Drugs Market is poised to ... reach approximately $12.8 billion by 2025. This industry ... on global as well as regional levels presented in the research scope. ...
(Date:2/23/2017)... MARIETTA, Ga., Feb. 23, 2017  MiMedx Group, Inc. ... amniotic tissue and patent-protected processes to develop and market ... Orthopedic, Spine, Sports Medicine, Ophthalmic, and Dental sectors of ... quarter and full year ended December 31, 2016. ... Revenue is a 31% increase over full year ...
Breaking Medicine Technology: