Monday, December 14, 2009

Tuberculosis research discovery lends hope for autoimmune diseases

Researchers at the University of Washington discovered that a protein secreted by skin and mucous membranes (wet and dry epidermis) called MMP9 causes infections to be more severe. Blocking it in mice leads to less inflammation and less disease.

Perhaps it will become a target for autoimmune diseases as well. I cannot help wondering if my susceptibility to infections and my son's terrible set of autoimmune diseases might be tied to a biochemical pathway that has this or a similar protein in it.
I go to another ENT tomorrow. I still have an active infection in my nose that is 'controlled' by the topical I put way up inside but not killed. It is painfully bloody high up inside. The topical in now being noticed by my insane immune system and I am beginning to itch intently, but have no choice but to use it. I will try to get Zyvox, a new pill antibiotic, but its use is restricted. I went to the ER today to talk to the doctor I saw a week ago that gave me the sulfa drugs that caused my immune system to itch so violently, but after parking in the lot and getting out of the truck, I just could not get up the courage to go in. There were so many sick people and I just could not get over an illness. Stupid in the 21st century to force immune compromised folks to go to the most infectious dangerous places to get care. Why not use the computer. i have a camera built in to this one. Most do now a days. Doctors sure do not like to change practices.

Instead of the ER I drove to a nearby salt water lagoon near the corner of Highway 78 and Interstate 5 I had not been to since I memorized all the names and photos of California birds a couple of years ago. I have been housebound for eight years. I used to get bored sometimes and it was fun memorizing the pictures and names in a couple of bird books. At the lagoon, I saw a Belding or Savannah sparrow at the edge of the road, western Grebe in the middle of the lagoon, and I am pretty sure I saw a Sora come out of the reeds for a second and go back in. Great birding as they say.

Here is the article: The URL is at the end of the article.

Finding How To Block The Infection Pathway May Lead To New Therapies For TB And Other Disorders
12 Dec 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."

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

Source: Leila Gray
University of Washington

Article URL:

Main News Category: Tuberculosis

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