Certain types of bacteria are particularly good at evading our immune systems, but a Dublin team is shining a light into their hiding places, writes CLAIRE O'CONNELL
SOME BACTERIA ARE downright crafty. They trick the body’s normal defence system, punching their way out of its clutches, hiding from antibiotics and causing potentially life-threatening diseases such as food poisoning or tuberculosis.
But scientists are closing in on them. Thanks to advances in light-based and imaging technologies, researchers are now watching up close and in real time as invading bacteria practise their stealth.
Working out how the bacteria get past the body’s guards could lead to improved therapies against these stubborn pathogens, according to Prof Sergio Grinstein, who visited Dublin recently to help launch the new €30-million National Biophotonics and Imaging Platform Ireland. Biophotonics involves using light-based technologies for biological and medical research and diagnostics.
“If you have a bacterium that interferes with the process, you want to know where and how it is interfering, because if you don’t know the mechanism, you won’t know how to treat it,” says Grinstein, who is professor of biochemistry at the University of Toronto. “We have been very successful at fighting infections with antibiotics for the last 50 or 60 years, but if you look at the development of antibiotics in the last 10 to 20 years, the rate has slowed down dramatically because all the obvious pathways have been explored.
“At the same time bacteria have developed resistance, so we have to think about new strategies that are not going to be dependent on antibiotics. We need to know where the bacteria are going and what they are doing in order to have more intelligent, rational designs.”
His research looks at how bacteria interact with white blood cells called macrophages, which usually recognise, eat and kill invaders. The process through which a macrophage engulfs a bacterium into an internal bubble or “phagosome” and kills it provides a perfect model for viewing under the microscope, explains Grinstein.
“It’s of a size and a temporal scale that is manageable by imaging techniques. You can see it in human time,” he says.
Of particular interest is how macrophages interact with rogue bacteria, such as the food-poisoning bug, listeria, which can knock a hole in the phagosome to escape it, or mycobacterium, which can hide dormant within the immune system for years before triggering TB.
“We are looking at both from the point of view of the host cell and the pathogen,” says Grinstein. “A number of pathogens have evolved mechanisms to survive by either bypassing or co-opting the responses of the macrophages.”
Using combinations of biochemical and imaging techniques, Grinstein tags proteins and fats of interest with visible probes and watches as macrophages capture bacteria and other particles under the confocal microscope, which scans specimens with a laser to build up high-resolution three-dimensional images.
“You can look at living processes with less damage to the cell,” says Grinstein. “And the technology is now sensitive enough and the computational techniques are sophisticated enough that you can track individual molecules. You can see phenomena that are extremely localised and fast.”
His work has recently focused on how the fatty cell membrane environment affects interactions between a macrophage and a potential invader. “A lot of our effort has gone into looking at lipids , and they turn out to be critical for the response. They are essential signals and there was no way of looking at them before,” he says.
Grinstein showcased his research – including movies of fluorescently tagged molecules lighting up as macrophages “eat” particles – at the launch of the National Biophotonics and Imaging Platform Ireland at the Royal College of Surgeons (RCSI) late last month.
Funded for four years by the Higher Education Authority and led by the RCSI, the platform links nine Irish and three Continental third-level institutions and aims to harness investment in biophotonics and advanced imaging technologies, according to national co-ordinator Prof Brian Harvey.
“We cover the four major areas – molecular imaging at a very small scale, then imaging of cells and tissues, then imaging of animals, and finally at the fourth level it’s human diagnostic research imaging,” says Harvey, the professor of molecular medicine and director of research at RCSI. The national platform aims to increase expertise, develop new technologies and provide researchers with access to facilities, he adds.