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publicado em 06/09/2011 às 19h00:00
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Vaccine against tuberculosis eliminates bacteria in the liver of rats

Immunization was achieved with modified bacteria that, due to the absence of some genes can not resist the body's defenses

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A potential vaccine against tuberculosis was used to completely eliminate the bacteria causing the disease in infected tissues of rats. The vaccine was created with a group of bacteria that, due to the absence of some genes are unable to prevent the autoimmune system of the host. Once the first line of defense is activated, there is the firing of a more specific immune response that can protect against future infections.

The research, published in the September issue of Nature Medicine, was conducted by scientists at the Howard Hughes Medical Institute, Albert Einstein College of Medicine and Colorado State University, USA.

To make matters worse, some types of M. tuberculosis have become resistant to all drugs currently used against the disease. "We're back at the same stage before the existence of anti-TB drugs," says researcher William R. Jacobs, Albert Einstein College of Medicine.

The only vaccine in current use, called Bacillus Calmette-Guerin (BCG), has not been fully effective. Although Jacobs and other scientists have tried to change the BCG vaccine to make it more effective, "we were only able to slow the growth of M. tuberculosis. We can not kill it with a vaccine by now."

In the first part of the job, Jacobs and colleagues investigated a set of genes called ESX-3, found in all mycobacteria. Previous research has suggested that the mycobacterial ESX-3 need to protect the innate immune system of their host's, the defense against invading pathogens to respond quickly, but not specifically. Jacobs and his team wanted to see if the deletion of genes affect the virulence of the bacteria, but could not do this directly with M. tuberculosis, because the attacker can not live without this set of genes.

Instead, the researchers excluded the genes from a benign bacterium, Mycobacterium smegmatis, which can tolerate the deletion. They then infected some mice with this bacterium. Although the injected dose was high enough that the M. smegmatis genes with intact ESX-3 rapidly kill the rats, an equivalent dose of modified bacteria caused no damage - apparently because the immune system was able to find and kill the bacteria that lacked the ESX-3.

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

The research team has dubbed the modification of the M. Smegmatis from "IKE". Then they inserted genes ESX-3 M. tuberculosis in IKE version, creating a new type of M. IKEPLUS called smegmatis. They thought that this move would restore the ability of bacteria to evade innate declining immunization. To everyone's surprise - and the initial disappointment - not what happened. The strain was as susceptible as IKEPLUS IKE in relation to the immune response of the mouse. "We thought, 'Maybe we're looking the wrong way. Perhaps we have actually done is the ideal vaccine vector. We have the M. smegmatis causing Th1 immunity, and now that we apply tuberculosis antigens, these mice can be protected against the disease, "Jacobs said.

To test this possibility, researchers analyzed five mice immunized with IKEPLUS and five non-immunized. All were infected with massive doses of M. Tuberculosis. The animals were killed without immunization within five days and all mice immunized with IKEPLUS were still alive 40 days later. Two of the mice survived until 90 days IKEPLUS, and one of them lived to 343 days after infection with the bacteria.

The Jacobs group repeated the experiments with mice and compared the effects of IKEPLUS immunization with BCG vaccine. "We protect mice IKEPLUS better than BCG," says Jacobs. Moreover, when the researchers analyzed tissue from mice immunized with IKEPLUS who survived more than 200 days after exposure to M. tuberculosis, they found that the bacteria had been completely eliminated from the liver of animals.

"This is something I have dreamed for years, be able to get more protection and antibacterial immunity," celebrates Jacobs, whose group began to explore the mechanisms involved and found that the IKEPLUS induces a change in CD4 T cell response Also known as helper T cells, the CD4 T cells are white blood cells that activate and direct other immune cells. The next steps involve bringing to light details of the mechanism and improve the vaccine IKEPLUS.

The artigo is available for download in full (in English) in the journal Nature.

   Palavras-chave:   Tuberculosis vaccine    BCG    A bacterium    Research    Colorado State University   
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