Monday, 12 February 2018

Talk : Predatory bacteria to treat infection

Fascinating recent talk by Prof Liz Sockett on "Cafe Sci: Predatory bacteria to treat infection" which described research done by Prof Sockett and colleagues Chris Moore, Alex Willis and Dr Serge Mostowy looking at how certain types of bacteria can be used to fight infection, as can be seen in this BBC article on the teams research.

Prof  Sockett, together with charming and cuddly visual aids 

Prof Socketts talk had three major characters :

i) The bacteria Shigella, which causes dystentry and kills hundreds of thousands around the world each year.

ii) The predatory bacteria Bdellovibrio, which, although smaller, can attack Shigella by burrowing into the Shigella bacteria and eating it up from the inside. It then reproduces inside the remains of the Shigella bacteria, with the multiple, newly formed Bdellovibrio then bursting out from the husk of the Shigella in a manner that is perhaps best described as Alien-stylee. This whole process takes around 4hrs.

Bdellovibrio life cycle (credit)

ii) Zebrafish larvae, which are often used as a model organism in medical research because they share many similarities to humans in the way their bodily systems function and are easily studied, the latter quality helped by the larvae being transparent so that interactions within their bodies can be viewed as they happen with a microscope. To allow the small ~1-2mm long larvae to be viewed, they are anesthetised so that they are asleep, then placed on a pad of sticky agar in a water filled dish. Critically, dozens of larvae can be prepared for each experiment, and experiments typically last a few days. This means that sufficient data is generated for statistically significant trends to be determined (compare, for example, with trying to be sure about the validity of results of a test on just 5 mice).

A transparent Zebrafish larvae

Firstly, Prof Sockett and team looked at what happened when they injected just Dbellovibrio into the hind-brain of zebrafish larvae (they used the hind-brain as the blood-brain barrier would ensure that the bacteria would remain in this area during the test). The work was reported in the Open Access paper "Injections of Predatory Bacteria Work Alongside Host Immune Cells to Treat Shigella Infection in Zebrafish Larvae". In the image below you can see (on the left) that the numbers of Bdellovibrio bacteria decreases over time, as they are attacked by the larvaes own white blood cells and because they have no pathogen bacteria to invade and use for reproduction. And on the right you can see that none of the larvae died - showing the Bdellovibrio is not harmful to the larvae.

Effect of injecting Bdellovibrio only (credit)

Then the researchers injected Shigella bacteria that had been modified to glow green under UV light, as you can see below, they grew rapidly and killed many of the larvea after 3-4 days. Other work (with glowing white blood cells), showed that, for reasons not yet known, the larvae's white blood cell response was not activated by the Shigella.

Over time (left to right), when Shigella only injected,
 the Shigella bacteria grow and kill most of the Zebrafish larvae (credit)

Next, the team injected Shigella (green glowing) and Dbellovibrio (red glowing) and saw that the Dbellovibrio bacteria (red) attacked the Shigella and grew inn numbers, with the amount of Shigella (green) reducing over time. They were also able to see (in other research) that the Dbellovibrio provoked the immune system to respond, sending white blood cells to attack both the Shigella and the Bdellovibri - this was an unexpected bonus! One point that was made was that whereas antibiotics use a single line of attack to kill bacteria, and so are vulnerable to bacteria evolving resistance; predatory bacteria use many different attack techniques at the same time, which makes it hard for pathogens to build resistance to them. This is one reason why predatory bacteria have been able to survive for millions of years.

Over time (left to right) when both Shigella and Dbellovibrio injected,
 the Bdellovibrio (red) attack and kill the Shigella (credit)

They group found that the use of Bdellovibrio (together with the white blood cell response it triggered) increased survival rates of the larvae from just over 20% to around 60%, which is very encouraging.

Comparison of injection Shigella vs Shigella and Bdellovibrio (credit)

The work has spurred further research, and attracted further funding - but of course, many questions remain to be answered :

-The predator bacteria are not like antibiotics and are unlikely to work across the whole body. Instead, they are likely to be of most use in localised areas of infection or potential infection such as wounds.

-It is not clear whether the technology will work in humans

-Risks of allergies or inflammation when used in humans are a concern (although the fact that Dbellovibrio is already all around us suggest that the risk is low).

-If people have had prior exposure to Bdellovibrio will it still work?

It was a team effort

The next Cafe Science talk is on 12th March 2018 at the Vat and Fiddle Pub, Central Nottingham at 8.00pm

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