Researchers at the Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital (NKI-AVL) have made the discovery that tuberculosis and leprosy bacteria follow a different path into the host cell than that which for forty years scientists had always maintained.

The insight has huge implications for an understanding of these diseases and for more effective medicines to combat TB, leprosy and even cervical cancer.

High-resolution electron microscopes and tomography have enabled Peters, Van der Wel and their colleagues to map the cell's internal organisation. Knowledge of differing cell organelles that also play a role in the development of cancer is important when trying to understand fundamental cell processes. During research into the fagosome, a pustule in the cell, they stumbled upon the unexpected discovery that has turned research into TB and leprosy on its head.

Alternative path

Peters and his colleagues have demonstrated that the TB bacterium Mycobacterium tuberculosis follows a different path in the host cell than its weaker younger brother Mycobacterium bovis BCG, used as TB vaccine as well. The absorption of bacteria into cells is also known as fagocytose and is the process whereby the membrane of a cell envelopes the bacterium thus forming a pustule (fagosome) within the cell in which the enveloped bacterium can be securely stored.

Once inside the body BCG is stored in the fagosome but within two days the contagious TB bacterium bursts through the membrane wall of the fagosome. The bacterium falls freely into a cell landing in a food-rich environment where it rapidly multiplies. Peters and Van der Wel demonstrated how the leprosy bacterium burst forth in a similar way. Mycobacterium leprae is a sister of the TB bacterium.

Till now scientists thought that the fagosome acted as a reservoir whence not only the BCG vaccine but also the contagious bacterium slowly multiplied. Now, however, not only does it appear that the bacterium follows an entirely different path but also multiplies quicker when lying free inside the cell.

Cutting bacterium

The researchers discovered that when bursting out the TB bacterium that causes illness and the leprosy bacterium are able to cut the membrane wall of the fagosome. Whilst carrying out a double blind test they were able to establish that the RD1 area was involved in the process. This is where the bacterium genes lie that can cut through the membrane wall. Whilst mutating in the RD1 area the bacterium remained imprisoned in the fagosome but when the mutation was artificially repaired the bacteria were once again able to break loose. The researchers have now patented the RD1 area.

A vaccine to combat cervical cancer, TB and leprosy

This discovery has consequences when developing new medicines. The current BCG vaccine provides little protection because it provokes a weak immunological reaction. In contrast the TB bacterium provokes a strong immunological reaction through its alternative path. In follow-up research Peters at the NKI-AVL Hospital and Van der Wel at the Free University Amsterdam Medical Centre are planning to fix the current BCG vaccine so that, just like the TB bacterium, it will fall freely and land in the cell. They think that in this way more powerful, and hopefully less expensive, vaccines can be developed for the Third World to combat TB as well as cervical cancer and leprosy.

The Dutch Leprosy Foundation, the Netherlands Ministry of Foreign Affairs and a subsidiary of the Bill and Melissa Gates Foundation have financed this research.

Source: Netherlands Cancer Institute