Insights into tuberculosis using a tropical fish

The research has relied on using a small tropical fish, the zebrafish, that can develop a form of tuberculosis (TB) that closely resembles the human disease.   

The research, led by Dr Stefan Oehlers from Duke University Medical Centre in North Carolina, and supported by Professor Philip Crosier from the University of Auckland, has just been published in the latest edition of the world’s top scientific journal, Nature.

“This discovery may open up new avenues not previously considered in the development of drugs to treat TB,” says Professor Crosier.   

“The TB bug subverts the host’s normal biological processes,” says Professor Crosier. “It turns out that in a manner similar to how tumours promote the development of new blood vessels to enhance their own growth and survival, TB works in a comparable manner by promoting new blood vessels to form in the host.”

The TB causing germs, called mycobacteria, induce the formation of granulomas that are the hallmark of tuberculosis.

“The formation of these granulomas, that we can model in zebrafish, are almost identical to what you would see in humans,” he says. “As the fish are transparent the granulomas that form on the exterior surface of the embryonic zebrafish can be easily visualised.”

Researchers examined the development of blood vessels in the tuberculous granuloma in the zebrafish. These granulomas were characterised with necrotic cores and bore a striking resemblance to those of human tuberculosis, he says.   

Using microscopy in the transparent larval zebrafish, they showed that granuloma formation is intimately associated with new blood vessel formation. Drugs that suppress granuloma-associated new blood vessel development also reduced infection burden and limited disease dissemination.

“A lot of work globally has been done to find new drugs to treat TB,” he says. “This discovery offers a new target area or molecular pathway that had not been previously considered,” says Dr Crosier.

“Drugs that restrict the development of new blood vessels used in cancer therapy are very expensive so are not suitable for the widespread treatment of TB patients in, for example, Africa,” says Dr Crosier. “But this discovery presents the opportunity to screen for cheap, small molecules that might do the same job as the biological agents.”

Another co-author on the study in Auckland, Dr Kazuhide Okuda, (who recently gained his PhD at the University of Auckland and is supervised by Professor Crosier), says the research began after his visit to Duke University and discussions with his former colleague, Dr Stefan Oehlers (who also gained his PhD from Auckland), about blood vessel research in TB.

“I have quite a bit of experience in vascular biology, and we concluded that this was something worth exploring,” says Dr Okuda. “We have created a 3D structure view of how the TB granuloma works and this was important because it’s better for visualising how the angio-genesis happens and shows that it happens equally in arteries and veins.”

Source: University of Auckland