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Linking childhood diarrhoea and the onset of type I diabetes

Virologist Associate Professor Barbara Coulson explains how a common childhood infection could hasten the onset of type 1 diabetes.

DYANI LEWIS

Hi, I'm Dyani Lewis. Thanks for joining us. Over the course of our lives and especially during childhood illnesses tend to come and go. Toddlers will bring home a cold from day care one year, develop a mild skin rash the next and maybe get a bout of the flu a couple of years after that. In most cases our immune system dispenses with such infections and sees us through to recovery. No need for long term management or daily drug regimes. Childhood diarrhoea is usually one of these illnesses. It can be nasty but for the most part it's nothing more than an unpleasant rite of passage for small children quickly forgotten after a day or two.

Type 1 diabetes is in a different category altogether. Instead of being short lived Type 1 diabetes is a lifelong condition. After onset, which usually occurs in childhood, Type 1 diabetes requires daily injections of insulin and careful monitoring of diet and blood glucose levels.

Today on Up Close I'm joined by associate professor Barbara Coulson who has been investigating an intriguing link between a virus that causes short lived diarrhoea in children and the onset of Type 1 diabetes, a condition that stays with people throughout their lives. Barbara is Principal Research Fellow at the Peter Doherty Institute for Infection and Immunity and the Department of Microbiology and Immunology at the University of Melbourne. Welcome to Up Close Barbara.

BARBARA COULSON

Thank you. It's a pleasure to be here.

DYANI LEWIS

Barbara, Type 1 diabetes is an autoimmune condition far less well known than Type 2 diabetes. What actually happens in Type 1 diabetes to cause the disease?

BARBARA COULSON

Well I think most people would know that in Type 1 diabetes the condition occurs because a person is no longer producing enough insulin and so cannot deal with the glucose levels appropriately anymore. It's generally considered that the loss of insulin results from death of the cells that produce insulin and these cells are located in little islands called islets which are located in the pancreas.

The death of these cells means over a long period of time gradually the cells are dying and eventually it gets to the point where there are just too few to produce enough insulin and that's when the disease actually manifests but there's a long pre-clinical period where the disease is developing but there are no symptoms.

Now the reason why the cells are dying is, as I said, generally considered to be an autoimmune process and what this means is that the body is attacking itself. The main players in this process are particular immune cells called T cells and these T cells are like soldiers normally patrolling the body to detect foreign material that might be in the body including infections. But sometimes these T cells can be generated such that they will destroy normal cells because they've been generated in an aberrant way. When that happens, if those cells are generated in such a way that they attack the pancreas and the islet beta cells then that will lead to Type 1 diabetes.

DYANI LEWIS

What is it that makes people genetically predisposed? What's going on in their bodies that's different to people who don't have a genetic predisposition to Type 1 diabetes?

BARBARA COULSON

Well I don't think we understand everything that's going on but one of the perhaps important factors is that in their system their immune response becomes directed towards self and so instead of being entirely directed at foreign invaders they start responding to proteins in the islets.

And the reason why this can occur is that if there's some sort of effect on the islets such that the beta cells are damaged, and this could be an infection directly of the beta cells or it could be some other insult - chemical or indirect damage that could occur, if that happens the beta cells when they are damaged will release components of the cell that are normally inside the cell and never seen by the immune system.

Then the immune system will make a response to these components and that is the basis of the auto‑reactive cells that are found in people at risk of diabetes as they progress towards diabetes.

DYANI LEWIS

This is really a very different condition compared with the more common Type 2 diabetes isn't it?

BARBARA COULSON

It is a very different condition. The Type 2 diabetes, as I understand it, it doesn't normally have an autoimmune component at all. It's more a metabolic disease.

DYANI LEWIS

You're a virologist so you study viruses. When did virologists become interested in Type 1 diabetes, an autoimmune disease?

BARBARA COULSON

Well it began in the 1980s. People found that autopsy specimens of people who had died at the time of a Type 1 diabetes diagnosis, which happened in those days - obviously things are different now, but they found evidence of particular viruses called enteroviruses being present in the pancreas and so then interest in that particular virus family and others started then.

DYANI LEWIS

The virus you're particularly interested in is rotavirus. Could you tell us a bit about what rotavirus is and the illness that it typically causes?

BARBARA COULSON

Well, as you said in your introduction, you referred to gastroenteritis and that's what rotavirus causes. It's the main cause of severe gastroenteritis or diarrhoea and vomiting in children worldwide. I stress severe because rotavirus has a particular property of being able to cause severe dehydration in children under the age of two.

This is a life threatening condition if not immediately treated. So in Australia and developed countries mortality from rotavirus is extremely low but in developing countries mortality is quite high. Before the advent of vaccines, which have started to be used since 2007, around 500,000 children died specifically from rotavirus disease diarrhoea every year.

DYANI LEWIS

How do we catch rotavirus infection?

BARBARA COULSON

It's a very stable virus in the environment and the main route is through contaminated hands, contaminated objects. When children have diarrhoea it's quite hard to maintain good hygiene. Evidence has shown that it could be spread through the air as well, through aerosols potentially. And every child in Australia or elsewhere becomes infected by rotavirus by the age of three so it's a very common infection but not every child becomes severely ill.

DYANI LEWIS

Once you've had the infection in that very early stage of life does that mean that you don't get it then later in life? Do adults catch rotavirus at all?

BARBARA COULSON

Yes they do. The immunity that we develop against rotavirus is not long lived partly because there are very many different strains of the virus, a bit like influenza I guess. The immunity does not extend to all the strains so you are prone to get infected throughout life but it's usually the first time you encounter the virus that you have the highest chance of becoming severely ill. After that you may or may not have symptoms or the symptoms might be relatively mild. You might think you've had food poisoning. Adults can become quite ill though, particularly the elderly. They can become severely ill.

DYANI LEWIS

This is Up Close. I'm Dyani Lewis and in this episode we're talking about how a virus could trigger Type 1 diabetes with virologist Barbara Coulson.

Barbara, in looking at this connection between rotavirus and Type 1 diabetes you work on mice that are genetically predisposed to getting Type 1 diabetes. How closely does the diabetes in these mice reflect Type 1 diabetes that humans get?

BARBARA COULSON

Well the mice that we use have been used in many thousands of studies on Type 1 diabetes and they're considered to be the best available model. They share a number of physiological and immune characteristics of the disease and they provide a really good model for the human disease.

DYANI LEWIS

What happens when you infect one of these mice with the rotavirus? How does this affect the onset of diabetes?

BARBARA COULSON

It's quite interesting because if we infect mice as infants, which is a time when humans become infected and get severe disease, the mice also get severe disease caused by rotavirus, so they get severe diarrhoea. But their diabetes development, if we monitor them for six months, their diabetes development is reduced quite substantially.

If we take young adult mice that are about six weeks old there's no effect on their diabetes from the infection.

If we take older adult mice that already have started on their progression towards diabetes and have many of the immune markers that show that progression they have an infiltration of immune cells into the pancreas and these cells are surrounding the islets and preparing to attack. Those mice when they're infected they get accelerated diabetes onset so they develop diabetes faster than control mice.

DYANI LEWIS

Ultimately in Type 1 diabetes you do need that destruction of the insulin producing cells. Is the rotavirus actually killing those cells when you infect the mice?

BARBARA COULSON

Well no. We've done a number of studies and looked at a number of aspects of this and we do not find virus in the pancreas of these older mice. What we do find is evidence that the virus is replicating in the intestine, as we'd expect. We can find evidence that it's being carried presumably by immune cells to organs called regional lymph nodes and these are lymphoid organs where our immune cells congregate and communicate with each other. Each major organ in the body has one of these lymph nodes that drains that organ and the cells migrate from that lymph node to the organ.

In our case we find infectious virus or bits of the viral protein in the lymph nodes that drain the intestine and the pancreas. We also find evidence of immune cell activation at those sites.

DYANI LEWIS

So Barbara, in these lymph nodes around the intestine and pancreas you're seeing evidence that the immune system is fighting the infection but the infection never does get to the pancreas. What's going on with the immune system in those lymph nodes?

BARBARA COULSON

The virus is being taken up by a class of immune cells called dendritic cells as plasmacytoid dendritic cells actually. These cells are processing this virus in such a way that they are activated in function and they release a chemical called interferon and this Type 1 interferon is a very powerful antiviral protein. It then reacts with nearby cells, other dendritic cells and triggers their activation as well. So although the virus can only infect a very small proportion of the dendritic cells a large proportion of them become activated through this pathway.

If we then go outside the mouse, so if we then set up this scenario again say in a Petri dish essentially, in a cell culture dish, with the purified immune cell populations and we expose them to virus we can then recapitulate this activation. We also then see further activation of other immune cells called B cells which are important in antibody production and we see T cell activation as well. We have shown that specifically if there are islet auto‑reactive T cells present in the culture that those T cells become activated.

DYANI LEWIS

In the case of the B cells and the T cells being activated we're not just talking about cells that are specific to antigens on the rotavirus are we? They're not just there to fight the rotavirus?

BARBARA COULSON

That's exactly right. Through this particular mechanism that rotavirus induces any cells that are nearby where the interferon can diffuse towards, those cells can be activated even though they are totally unrelated to rotavirus and were present before the rotavirus infection occurred. We call this process 'bystander activation' because these bystander cells have specificity unrelated to the virus becoming activated.

What we believe is happening in the mice - this is occurring in the mice as well - is leading to activation of the auto‑reactive cells that are present and these auto‑reactive cells are then able to damage and kill the beta cells in the islets more quickly because their function has been increased and therefore this is behind the accelerated onset of diabetes that we see.

So these mouse studies, this has given us an insight into a mechanism by which rotavirus could be accelerating diabetes.

DYANI LEWIS
Not everyone's immune system will respond in this way, is that right?

BARBARA COULSON

Well that's very true because this process can only occur if there are pre‑existing auto‑reactive T cells. You'd need a reasonable number of those cells to be present too otherwise the probability of this occurring would be too low. This mechanism, we believe, is only really going to occur in children or people who already have been triggered to be well on the way towards getting diabetes.

DYANI LEWIS

You don't work directly with people who have diabetes. Is there a particular reason for that?

BARBARA COULSON

The reason why I got really interested in the possible link between rotavirus and Type 1 diabetes was because I was involved in a collaborative study some years ago with diabetes researchers here in Melbourne who had found in studying a large cohort of babies from birth born to mothers and fathers who had a close relative with Type 1 diabetes, and so at risk of developing the disease genetically, they'd been studying these children.

Through the samples they collected from these children and analysed they'd found that their T cell responses to islet auto‑antigens included responses to particular proteins that showed quite a strong similarity to a rotavirus protein.

This suggested that there might be a link and on that basis we went ahead and analysed the rotavirus infection history of all these children and we found that there was a temporal correlation, so a link in timing between a rotavirus infection and an exacerbation of the islet antigen autoimmunity that we could measure.

We did do quite a bit of work in children at that time. This was the first time anyone had shown this possible link. I actually decided to move from humans to mice to see if we could tease out what the mechanism really might be.

DYANI LEWIS

I'm Dyani Lewis and my guest today is virologist Barbara Coulson. We're talking about a link between rotavirus and Type 1 diabetes here on Up Close.

Barbara, for people who are in this preclinical stage of their body already creating these auto‑reactive T cells that will perhaps eventually destroy their islet cells, do all of those children go on to develop Type 1 diabetes or is it only something like a rotavirus infection that tips them over the edge?

BARBARA COULSON

Well clinicians, researchers now are to use a number of markers that they can test for in people's blood to see their level of risk towards developing diabetes given they've got a genetic background of this and that they've been involved perhaps in a clinical trial and so they're being evaluated prior to any disease. With time, as the progression continues, more and more of these markers can be detected and the probabilities now are known so it could be predicted what the probability is but it's not absolute so of course not all children who are at risk will develop Type 1 diabetes.

And that's why we're looking so carefully at environmental influences because genetics doesn't even explain 50 per cent of the Type 1 diabetes that's seen. There's a very strong environmental influence and it could be that over time, depending on a child's exposure to a number of different environmental insults if you like including, but not limited to, viruses - a number of other things, that that might be a tipping point or in some cases the children just develop a certain level of autoimmunity and then it just stabilises. And I don't know that it's fully understood why that is.

DYANI LEWIS

You mentioned earlier that there's a rotavirus vaccine that's now available. Could this also trigger the onset of Type 1 diabetes for those people who are in that preclinical stage of getting the diarrhoea?

BARBARA COULSON

Well I think that would be extremely unlikely. The vaccines that are currently available are live, attenuated viruses so the virus can replicate in the intestine of the child but only to a very limited extent because it's been essentially disabled. The small degree of replication that it does undergo is sufficient to induce a good immune response and that is the basis of the very good protection that these vaccines give. And the evidence for the protection they're giving is very strong. In Australia hospitalisations have more than halved for rotavirus and it's a great outcome.

Because this vaccine virus is disabled it replicates at a low level and our work in mice has very clearly shown that you need a good level of virus replication, a high level of virus replication before the virus is able to accelerate diabetes. I would say it's extremely unlikely that the current vaccines could have a detrimental effect.

I think it's more likely the current vaccines could have a positive effect because they're going to replace this first infection in a child, that could be a severe one with a high level of virus replication, with a mild asymptomatic challenge with low level of virus replication. That may actually prevent some accelerated diabetes from happening.

DYANI LEWIS

Do you think that maybe there might be a drop in Type 1 diabetes with the introduction of the vaccine?

BARBARA COULSON

It's certainly a very important question and it's possible. It's possible that that could happen although the vaccine is given to children at such a young age that it's not possible they would have already started developing their islet autoimmunity. And in that scenario it's possible that it could be protective but it also, as we saw in our mice that were young adult, there was no effect. You can't really extrapolate so closely from mice to humans in terms of the aging process. It just doesn't make sense.

So I think we really have to just examine that question but it's possible there might be some effect or, I guess the worst case scenario, maybe it would just be the same. But it's a very important question and it's something that we really want to look at.

DYANI LEWIS

Just a final question then. What does your research mean for children who might have this genetic predisposition for Type 1 diabetes? What's the ultimate goal of your work of picking apart this immune response that's happening?

BARBARA COULSON

Well if we can understand how the virus is having its effect then that gives us the ability to very specifically target what's going on, for example try and prevent activation of certain of these immune cell types from occurring. And in fact this ties in very nicely with important goals for diabetes researchers generally who have identified excessive immune cell activation generally as a mechanism that's potentially involved in Type 1 diabetes as something that they would like to dampen down.

Coming at it from the viral side or from just the Type 1 diabetes mechanism generally, it seems like we're coming up with the same sort of ideas on how to approach it. These other diabetes researchers are developing approaches to intervene to dampen down excessive inflammation and immune cell activation. That could well have a positive effect on the virus side as well.

DYANI LEWIS

Perhaps prolonging the amount of time that people are disease free?

BARBARA COULSON

Absolutely yes and I think potentially if one can attack a number of the environmental antigens of perhaps several different viruses that are implicated one might be able to substantially prolong the diabetes free period of children. That has a lot of implications for their lifestyle but also for their chances of developing complications later on. So it could make a big improvement for the life of people who are living with Type 1 diabetes.

DYANI LEWIS

Barbara, thanks for being our guest today on Up Close.

BARBARA COULSON

Thank you.

DYANI LEWIS

Associate professor Barbara Coulson is Principal Research Fellow at the Peter Doherty Institute for Infection and Immunity and the Department of Microbiology and Immunology at the University of Melbourne.

If you'd like more information or a transcript of this episode head to the Up Close website. Up Close is a production of the University of Melbourne, Australia created by Kelvin Param and Eric van Bemmel. This episode was recorded on 29 April 2014. Producers were Eric van Bemmel, Kelvin Param and myself, Dr Dyani Lewis. Audio engineering by Jeremy Taylor.

Until next time, goodbye.