BioWorld International Correspondent

LONDON - New insights into how the tuberculosis bacterium interacts with cells of the human immune system could aid the development of novel vaccines and immunotherapies to combat the disease.

Mycobacterium tuberculosis uses one of the same receptors as HIV to enter cells of the immune system, researchers have discovered.

The receptor, called CCR5, helps to modulate the immune response to the infection. One strategy for new treatments could be to boost that response, strengthening the ability of immune system cells to deal with the bacterium.

Paul Lehner, professor of immunology and medicine and Wellcome Trust senior clinical fellow at the Cambridge Institute for Medical Research in Cambridge, UK, told BioWorld International, "It is a very significant finding that both HIV and mycobacteria are co-opting the same cellular receptor, and the work we report is generally important for understanding the basic biology of mycobacterial recognition by cells of the immune system."

An account of the study appears in the Oct. 19, 2006, issue of Science, in a paper titled, "Dendritic Cell Stimulation by Mycobacterial Hsp70 Is Mediated Through CCR5."

Lehner and his team had been studying the role of heat shock proteins in triggering immune responses to infection. Earlier work by others suggested those proteins might be able to bind immunogenic peptides and deliver them to the cell.

"We wanted to know how the heat shock proteins were able to do this," Lehner said. "Did they use specific receptors?"

The team screened a variety of heat shock proteins and discovered that one from M. tuberculosis, called myHsp70, could stimulate dendritic cells efficiently and effectively.

Using pharmacological inhibitors, the researchers narrowed down the receptors that myHSP70 might be using to a G protein-coupled receptor, before finally pinpointing the receptor as CCR5.

CCR5 is found on cells of the immune system, particularly T cells, dendritic cells and macrophages. "CCR5 is a really crucial chemokine receptor of the immune system," Lehner said.

Data presented in the Science paper suggest that signaling via CCR5 appears to control, at least partially, the ability of M. tuberculosis to replicate inside dendritic cells. In one experiment, inhibition of CCR5 signaling resulted in enhanced intracellular mycobacterial replication.

Beate Kampmann, a Wellcome Trust fellow at Imperial College London and one of the co-authors of the paper, told BioWorld International: "The interactions between mycobacteria and host cells are an enormous jigsaw, and this study describes another quite chunky piece of that jigsaw. It is important for us to know what happens inside the cell following this interaction, because only with this knowledge can we design effective drugs and vaccines."

The study used a luminescent version of mycobacteria, developed by Kampmann, to assess the growth of the bacteria.

Kampmann also is senior lecturer in pediatric infectious diseases. One of her concerns is what the discovery will mean for people who may in the future be treated with drugs that inhibit CCR5.

CCR5 inhibitors are a completely new class of anti-HIV drugs, currently being evaluated in clinical trials. HIV uses both CD4 and CCR5 to enter cells; people with a mutation in the gene encoding the CCR5 receptor are resistant to HIV infection.

"The worry is that by inhibiting the receptor in people who are also exposed to tuberculosis, we might be sidelining one of the mechanisms that people use to fight off tuberculosis," Kampmann said.

She emphasized that this risk remains theoretical, as the drugs still are in trials. But a similar problem already cropped up with treatments that damp down the release of tumor necrosis factor (TNF). Following that type of therapy, which now is used widely for patients with rheumatoid diseases, several people who presumably were already latently infected with tuberculosis developed active disease.

Kampmann said: "This has happened because the anti-TNF treatment paralyzes their TNF pathway, which has a known role in the combat of mycobacteria. In clinical practice, we now need to determine who is already infected with tuberculosis, before prescribing these anti-TNF treatments. Following this latest finding, I can foresee something similar happening if CCR5 inhibitors were to be given to HIV-infected people who are also infected with M. tuberculosis. These drugs are far from being rolled out in TB-endemic countries, but we need to be aware of the potential risks as we were completely caught out with the anti-TNF therapy."