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June 29, 2009- Tuberculosis (TB) experts at Johns Hopkins have evidence from a four-year series of experiments in mice that anti-inflammatory drugs could eventually prove effective in treating the highly contagious lung disease, adding to current antibiotic therapies.
The Johns Hopkins scientists are planning further experiments in animals infected with TB to find out if any of the already-approved anti-inflammatory drugs -- phosphodiesterase (PDE5A) inhibitors, such as sildenafil citrate (Viagra) and adenylate cyclase (AC) inhibitors – would work.
The new study results, to be reported in the July 2 issue of Nature, not only offer promise of a complementary or alternative therapy to antibiotics, but also open the door to vaccines designed to block the TB bacterium’s inflammatory chemical pathways, the researchers say. The disease, caused by Mycobacterium tuberculosis, each year infects nearly 9 million people worldwide, and kills 1.7 million.
The research team bases its claim on their recent studies in mice showing precisely how disease-causing TB bacteria provoke an inflammatory response in immune system cells and surrounding lung tissue, and that blocking the action of a key inflammation-triggering enzyme, a type of adenylate cyclase, stalled TB disease.
The scientists say their findings are believed to be the first and most detailed explanation of how the invading bacterium evades the immune system and instead is protected by it, thus fostering infection.
“Traditional approaches for treating TB have focused on using antibiotics to directly target and kill the bacterium after infection, eventually ridding it from the body, whereas our results suggest a new route to interrupt post-infection inflammation and disease progression, thus hindering bacterial spread within tissues,” says study senior investigator and infectious disease specialist William Bishai, M.D., Ph.D.
The new study showed how the highly contagious bacterium evades macrophage immune system cells meant to destroy it, by spiking production within the infected cells of inflammation-triggering chemicals, such as cyclic-adenosine monophosphate (cAMP) and tumor necrosis factor-alpha. Production of TNF-alpha is largely stimulated by cAMP, which is secreted into infected cells by the bacterium, and TNF-alpha signals other immune system cells to attack and isolate infected cells, a key part of inflammation.
In people with TB, Bishai says, the process produces a “paradoxical effect.” Instead of acting as a natural defense against the pathogen that cordons off the bacterial infection, the increased inflammation produces tiny, telltale lesions of dead lung tissue that harbor pools of live bacteria.
Bishai, a professor at the Johns Hopkins University School of Medicine, notes that it has been known since the 1920s that inflammation and small, lung granulomas were a key part of TB disease, and since the 1970s that TB infection elicits an initial spike in cAMP levels inside infected cells. Until now, however, scientists had assumed that this burst of cAMP was simply the cells’ initial response to the lung tissue damage caused by TB disease. “We were surprised to find out that this inflammation was the result of the microbe manipulating macrophages and causing the spread of TB,” he says.
In the first series of experiments, the TB team, led by Nisheeth Agarwal, Ph.D., a postdoctoral research fellow in infectious diseases at Hopkins, tracked that first burst of cAMP directly back to the time of initial infection. Tests of live and dead bacteria showed that only live bacteria produced any initial uptick in the inflammation-signaling chemical, in which macrophages were tested in the lab at several hourly intervals post-infection.
Realizing then that this chemical burst of activity could play a key role in spreading the infection, the Johns Hopkins team set out to determine what, if any, other downstream inflammatory reactions occurred, as cAMP production is well known to rev up production of other inflammatory chemicals, most notably, TNF-alpha.
Further experiments by the team identified the gene mostly responsible for these boosted levels of cAMP, linking its unique hyperactivity to at least one of 17 signaling enzymes, adenylate cyclases, which stimulate cAMP production. Bishai’s interest in the enzymes -- in particular, the adenylate cyclase whose production is tied to gene Rv0386 -- was prompted by the fact that M. tuberculosis has so many of them. Most bacteria have only one.
Blocking Rv0386 led to a 10-fold drop two months after TB infection in the number of bacteria seen in mouse lung tissue samples, extracted and then grown in the lab, when compared to infected mice with unhindered Rv0386 production. Less active Rv0386 also led to as much as an 80 percent drop in macrophage cAMP levels, plus a 50 percent decline in infected cell secretions of TNF-alpha, which Agarwal says “indicates a much milder case of TB disease.”
Agarwal says the team’s immediate next steps are to map out the full biochemical equation in the spread of TB within the body, most notably how upped production of TNF-alpha manifests disease progression. This, too, he says, could lead to “even more novel inflammatory targets for drug and vaccine development.”
TB remains the leading cause of death worldwide among those with HIV and AIDS and is epidemic in developing countries with the highest HIV-infection rates. The nonprofit Global Alliance for TB Drug Development estimates that 1 billion people worldwide will be infected with tuberculosis by the year 2020. Conventional TB therapy is considered cumbersome, even though it cures on average 95 percent of patients who finish taking their medications as originally prescribed. Standard treatment consists of a mix of antibiotics, typically four, given in view of a caregiver and taken together for six months.
Bishai and colleagues conducted their research from 2005 through 2008 with funding from the U.S. National Institute of Allergy and Infectious Diseases, a member of the National Institutes of Health.
Besides Bishai and Agarwal, other researchers from Hopkins involved in this study were Gyanu Lamichhane, Ph.D.; Radhika Gupta, M.Sc.; and Scott Nolan, B.Sc.
Media contact: David March