Fungal spore functions as biological body tracer

Interview with Dima Hammoud, NIH Clinical Center

Part of the show Pager attacks in Lebanon, and resurrecting ancient seeds

Researchers in the United States have developed an imaging agent which can track down deposits in the body of the relatively common fungal infection called aspergillosis, which can spell disaster for patients with compromised immune systems. The study - which was carried out on mice - has recently been published in the journal Science Translational Medicine, and it hinges on using a small radioactively-labelled sugar molecule that the fungus can take up and digest but which our own tissues cannot use. As such, it concentrates at the fungal infection site, producing a “hot spot” that a PET scanner can see. Dima Hammoud is the brain behind the breakthrough and she’s at the NIH Clinical Center…

Dima - Aspergillus is actually found everywhere in the environment. We do inhale it every day, but because we have a competent immune system, we are able to eliminate that microbe immediately before it starts germinating and growing. But when those patients with weak immune systems inhale Aspergillus, the spores are not efficiently eliminated and then they start growing and they start invading and become deadly infections. So it's very important in those situations to actually diagnose fungal infections really early on because you want to start them on treatment very fast as soon as possible and that will give you the best results.

Chris - And where does your work fit into that?

Dima - I am a radiologist and my research is in PET imaging, which is short for positron emission tomography. And the reason we were first interested in this is because fungal infections are very difficult to diagnose. So if you do a CT scan or MRI, you might not be able to differentiate a fungus from a bacterium and then you don't really know what to treat them with. Also, you might need biopsies or you need to be really invasive to get those. So that's what kind of prompted us to think of a non-invasive study, like an imaging method that will tell us specifically if there are fungal infections in those patients. And if there are, we can start treatment really rapidly and get better results.

Chris - So almost like a marker that will flag up where they are if they're there and make them go on like a bright red warning light to you, the radiologist.

Dima - Yeah. So a lot of people, especially cancer patients, are very familiar with PET imaging because they get something called FDG PET. And FDG is essentially a molecule. It's a glucose molecule that somebody added a radioactive tag to. And what happens in cancer patients, you inject FDG and then you do the scanning and then you detect where it went because it has a radioactive signal. So what we wanted to do is to develop something similar to FDG, but that thing, instead of detecting tumours, it'll actually go after fungi, like Aspergillus, as I said. because it's one of the worst fungi to infect immunosuppressed patients.

Chris - So how do you target it in that way? What have you exploited about the fungus that means you can do that?

Dima - We looked very carefully at what fungi eat. Fungi are everywhere in the environment and they have to survive. It's not always easy to find food. So as a result, they evolved to be able to use sugars other than glucose, especially those found in plants. And those are really very complex sugars called cellulose, which are like sheets of sugars. So fungi actually dissolve those sugars, by using special enzymes, into smaller pieces. And smaller, smaller, smaller. The last sugar in this reaction is one called cellobiose. So when we started looking at Aspergillus, we thought cellobiose might be a good idea because essentially it's made of two glucose molecules that are very strongly tied together. So much so that humans and other microbes like bacteria cannot break the bond between the two glucose molecules. Only certain fungi, on the other hand, like Aspergillus, can break cellobiose into two glucose molecules because they have those enzymes. So we thought if we actually can take this molecule cellobiose and attach a radioactive tag to it and then inject it in mice that have fungal infections, we should be able to see if it's broken into glucose and FDG by using a PET scanner. The PET scanner we use is actually a small kind of a miniature scanner from the human one. It's only for mice and rats. So what we do is we infect the mice and then we image them after we inject our molecule. And then we had another group of mice that were infected with bacteria, different types of bacteria, and then another group of mice that had inflammation, which is non-infectious. So we injected our molecule, the cellobiose molecule, which has a radioactive tag on it in those animals, and we imaged them and we found that only the animals with fungal infection are the ones that had radioactivity. All the other animals just injected that thing in and it went immediately out. There was no accumulation. So that confirmed our theory that only fungi, specifically Aspergillus in this case, are capable of breaking cellobiose. And that's why you get this accumulation of radioactivity.

Chris - And you're comfortable that that is not harmful when you inject that. It's not going to cause some kind of side reaction or problem for the person who ultimately might end up having it injected into them.

Dima - This is the basis of PET imaging. Anything we inject, including FDG, has to be in very, very small amounts. It's so small that it can never affect any organ or anything happening, any process either in the animals or in patients. FDG for example, it's injected in very, very tiny amounts. And that's the same case with cellobiose.

Chris - So is the basis of this that if you have a deposit of fungi somewhere, because they are capable of metabolising this stuff, they're going to accumulate it. So you inject it, it goes all around the body, but where the fungi are, they're going to grab it, hold onto it, and start to break it down. And that's why you get a hot spot on your PET scan where they are.

Dima - When we inject it, it's in the blood, so it goes everywhere, but wherever it runs into Aspergillus, into a fungus, the fungus notices it and then starts producing that enzyme, breaks it and then takes it in. And that's why it accumulates while bacteria, they see it, but they can't do anything about it. So it just goes away.