September 8, 2011

Vaccine Could Wipe Out Tuberculosis

(Ivanhoe Newswire) — A potential vaccine against tuberculosis (TB) has been found to completely eliminate TB bacteria from infected tissues in some mice. The vaccine was made from a strain of bacteria that are unable to avoid its host´s first-line immune response. Once this first-line defense has been activated, it triggers the more specific immune response that remembers the bacteria and protects against future infection.

Tuberculosis, an infectious disease caused by Mycobacterium tuberculosis, is a global health concern, accounting for 2-3 million deaths annually. One third of the world's population is infected with the bacterium, and according to the World Health Organization, new infections occur at a rate of about one per second. Most people who are infected don't get sick, because the immune system keeps the bacteria under control. However, people whose immune systems are weakened, such as those with HIV/AIDS, are highly susceptible to the active form of the infection. With staggering rates of HIV infection in some parts of the world, such as Africa, co-infection with TB is a serious problem. To make matters worse, some strains of M. tuberculosis have become resistant to every drug currently used to treat tuberculosis.

"We're back to where we were before there were drugs for TB," William R. Jacobs, Jr., an HHMI investigator at Albert Einstein College of Medicine, was quoted as saying.
The only vaccine in current use, called Bacille Calmette-Guérin (BCG), hasn't been consistently effective at protecting against the disease.

In the first part of the work, Jacobs and colleagues investigated a set of genes called esx-3 that is found in all mycobacteria. Previous research had suggested that mycobacteria need esx-3 to protect themselves from their hosts' innate immune systems, a first-line defense against pathogens that responds to invaders quickly, but non-specifically. Jacobs and his team wanted to see if deleting the genes would affect the bacterium's virulence, but they couldn't do this directly with M. tuberculosis, because the bug can't live without that set of genes. Instead, the researchers deleted the genes from a closely related, but usually benign bacteria, Mycobacterium smegmatis, which can tolerate the deletion. They then infected mice with the M. smegmatis bacteria. Although the dose they injected was high enough that M. smegmatis with intact esx-3 genes rapidly killed the mice, an equivalent dose of the modified bacteria caused no harm -- apparently because the immune system was able to find and kill bacteria that lacked esx-3.

These findings suggested that esx-3 plays a key role in protecting M. smegmatis from innate immunity. A key feature of innate immunity is that unlike the second branch of the immune system, adaptive immunity, innate immunity does not confer lasting protection against subsequent infections by the same pathogen.

The research team dubbed their modified strain of M. smegmatis "IKE" for immune killing evasion. Next, they inserted esx-3 genes from M. tuberculosis into the IKE strain, creating a new strain of M. smegmatis they called IKEPLUS. They thought this maneuver would restore the bacterium's ability to evade innate immune killing. To their surprise — and initial disappointment — that wasn't what happened. The IKEPLUS strain was just as susceptible as IKE to the mouse immune response.

The researchers gave five IKEPLUS-immunized mice — and a control group of five unimmunized mice — massive, intravenous doses of M. tuberculosis. All five of the unimmunized mice were dead within five days; all the IKEPLUS-immunized mice were still alive 40 days later. Two of the IKEPLUS mice survived to 90 days, and one of those lived to 343 days after infection with M. tuberculosis. Jacobs's group repeated the experiments with more mice and compared the effects of IKEPLUS immunization with those of BCG immunization.

"We consistently protected mice better with IKEPLUS than with BCG," Jacobs said. What's more, when the researchers analyzed tissues from IKEPLUS-immunized mice that survived more than 200 days after exposure to M. tuberculosis, they found that the bacteria had been completely eliminated from the animals' livers.

"This is something we've dreamed about for years, to be able to get longer protection and bactericidal immunity," explained Jacobs.

The next steps will be teasing out additional details of the mechanism and improving the IKEPLUS vaccine.

SOURCE: Nature Medicine, September 2011.