Deadly disease can ‘hide’ from a Tasmanian devil’s immune system

Andrew S. Flies, University of Tasmania and Greg Woods, University of Tasmania

The Tasmanian devil facial tumour (DFT) cells may use a molecular deception – common in human cancers – that could allow the deadly disease to avoid the animal’s immune system, according to our new research published this month.

Recently it was discovered that DFT cells effectively hide from the immune system by not expressing key immune recognition molecules.

Our new discovery that DFT cells contain this “molecular shield” in response to inflammation represents another important step towards understanding the disease and developing more potent ways of preventing or treating it.

So how does this shield work? First, we need to look at some of the recent developments in the treatment of cancers in general.

Cancer treatments

Cancer treatment has undergone a revolution in recent years. Gone are the days when surgery and harsh chemotherapy regimens are the only options.

Now cancer immunotherapy can stimulate the immune system to kill cancer cells. In 2013 this was named the breakthrough of the year in one of the top science journals in the world.

Since 2013 the immunotherapies that target what we call immune checkpoint molecules have continued to make great progress and have recently been approved as first line defences for some cancers.

Checkpoint molecules are critical for keeping the immune system in balance. Every time that the accelerator is pressed in the immune system, there is always at least one, and often several, means of stepping on the brakes.

These checks and balances are necessary because even though the primary job of the immune system is to protect us from disease, the immune system wields powerful weapons that can inflict collateral damage to critical tissues and organ systems when it is aimed at the wrong target.

Programmed death

In recent years the aptly-named checkpoint molecules – “programmed death-1” (PD-1) and “programmed death ligand 1” (PD-L1) – have emerged to be critical regulators of the anti-cancer immune response.

The PD-L1 molecule is used by many types of cancer as a molecular shield to protect the malignant cells from anti-cancer immune responses.

The PD-1 molecule is found on several types of immune cells, but has particular relevance to the anti-cancer responses mediated by T cells.

When PD-1 on a cancer-killing T cell interacts with PD-L1 on cancer cells, the T cell is shut off. The T cell may undergo programmed death or it may linger and play no role in the anti-cancer response.

The worst possibility is that the former cancer-killing T cell hangs around and actually prevents other immune cells from killing cancer cells.

The Tassie devil’s immune system

Our Tasmanian devil immunology team has recently demonstrated that these critical immune checkpoint molecules are also present in devils. This may play a role in the ability of the DFT’s ability to evade the devil immune system.

There likely exists many additional mechanisms that the DFTs use to hide from or suppress the immune system of devils and ongoing research efforts aim to uncover and neutralise these mechanisms.

Recent evidence has shown that some devils have tumour regressions, showing that the tumours are not always able to hide from the immune system.

Spontaneous tumour regression is not common in humans, but it does occur in some people and is likely caused by the immune system recognising and killing tumour cells.

Another deadly disease

But the devils are not out of the woods yet for a few reasons. Only in 2014 a second transmissible cancer (devil facial tumour disease 2 or DFT2) was discovered in wild devils in southern Tasmania.

There are only a handful of naturally transmissible tumours known in the world, so a second transmissible tumour in devils is extremely surprising, like lightning striking the devils twice.

In order for the wild devil population to be truly safe from the transmissible tumours, they would need to have immunity to both the original transmissible tumour DFT and DFT2 and hope that no new transmissible cancers arise.

It remains unknown at this point how many different weapons the tumours use to evade or suppress the immune system.

The tumours themselves can also evolve rapidly in response to ecological and immunological pressure. In many cases, disease causing agents evolve to be less virulent (not kill the animal they infect), but only time will tell if that will happen in the curious case of the devil.

Our ongoing research aims to understand exactly which devil immune system switches can be turned on and off in order to stimulate immune cells to kill cancer cells.

This will be particularly fruitful if we can pinpoint specific genetic and immunological mechanisms that are different in devils that kill tumour cells and those that don’t.

It’s not often that you cheer for the devil, but this is one situation where nearly everybody wants the devil to win!

The Conversation

Andrew S. Flies, Postdoctoral Research Fellow in Immunology, University of Tasmania and Greg Woods, Professional Research Fellow, University of Tasmania

This article was originally published on The Conversation. Read the original article.

Tasmanian devils reared in captivity show they can thrive in the wild

Tracey Rogers, UNSW Australia

One of the concerns of any conservation breeding program is how well a species raised in captivity will survive when released into the wild.

Evolutionary changes that are beneficial for an individual while in captivity may reduce its fitness when translocated to the wild.

For some species, like many fish, rapid evolutionary changes can occur within the first generation in captivity. And carnivores raised in captivity have a low chance of surviving the first year following their release.

A review of 45 carnivore translocations, which included 17 different species, including the European lynx, European otter and the swift fox, found that if the animals had been raised in captivity they had on average a 30% chance of survival after release.

Save the devil program

All this was a concern then for efforts to help save the Tasmanian devil.

The devil plays an important functional role within the Tasmanian ecosystem and is the last of the large marsupial carnivores.

But the Tasmanian devil is listed as endangered and their population has declined by 80% over the past ten years. This is due largely to the infectious fatal cancer, the devil facial tumour disease (DFTD).

As part of a conservation effort, a disease-free devil population has been established in captivity.

But given the low rate of survival of released captive-raised carnivores in other conservation programs it was important to identify whether their release could play a viable role in the conservation of the Tasmanian devil.

Captive breeding programs are extremely expensive and resource allocation was very tight. So more than 35 institutions helped to set up the captive devil insurance population.

Different types of enclosure setting were used, some intensive zoo style while others had larger pens to allow for a more free range style. The different enclosure types offered different opportunities for the devils to retain their natural behaviours.

We tested the effect of the various captive-rearing methods on the survival and body mass of captive raised Tasmanian devils that were released on Maria Island, off Tasmania’s east coast.

Our study, published this month in CSIRO Wildlife Research, showed that Tasmanian devils raised in captivity before being translocated into the wild had a high survival success (96%). Most of the devils are still alive two years after their release.

The devils gained weight, are hunting and breeding. This is irrespective of the type of captive-rearing method as both zoo style and free range reared animals are thriving.

Release of the devils.
Wildlife Management Branch, Department of Primary Industries, Parks, Water and Environment

Natural born killers

One cause of translocation failure in other programs has been that the released animals starve. The captive-raised animals had not learnt foraging and hunting skills. Some carnivorous mammals can lose this natural foraging behaviour in captivity.

But the captive-raised Tasmanian devils adjusted to the wild better than other carnivorous species. This was not only because they were released in the relative safety of an island, but it suggests that the devils’ foraging behaviour does not need to be learnt.

Devils have bone crushing jaws.
Wildlife Management Branch, Department of Primary Industries, Parks, Water and Environment.

Devils have a massive head with bone crushing jaws, large tough molars and strong shoulders and neck. They have a very broad approach to what they will eat.

Their diet includes all major critters such as mammals, birds, reptiles, amphibians and invertebrates. Devils have been seen catching gum moths out of the air, slurping tadpoles out of ponds and digging yabbies out of their burrows.

They also live from the intertidal zone to the sub alpine zone. They climb trees like a possum and are good swimmers.

There was less carrion available on Maria Island than on the mainland. Also the captive-raised devils would not have learnt hunting skills while in captivity so we presumed that they would not eat large prey.

Captive devils feeding upon a carcass.

Initially, after the first release, the devils fed on brushtail possums. But relatively soon after we found the devils started to feed on large prey, such as the common wombat and eastern grey kangaroo. These species are much larger than you would predict for a mammal of the devils’ size to prey on.

What’s planned for the devils?

So what does the success of this wild release say for the future conservation of the Tasmanian devil?

The devil facial tumour disease has been detected across the majority of the devil’s range. The wild devil population has been decimated as the disease moved across Tasmania.

It is time to boost the genetic diversity of the wild population. We need to provide the potential for immunity to develop in the species. That’s why it is exciting to have found that the captive-raised devils adjusted so well in the wild.

The next step will be to supplement the wild Tasmanian mainland population by releasing further captive-raised devils, along with those born wild on Maria Island.

But the devils released on the Tasmanian mainland will face other dangers. Alongside the disease they will have to contend with dogs, rodent poison and car collisions.

Clearly there’s some work still to be done, but the Maria Island and captive devils will continue to be an important part of the fight against the deadly facial tumour.

The Conversation

Tracey Rogers, Associate Professor Evolution & Ecology, UNSW Australia

This article was originally published on The Conversation. Read the original article.

Tasmanian devils are evolving rapidly to fight their deadly cancer

Menna Elizabeth Jones, University of Tasmania; Andrew Storfer, Washington State University; Hamish McCallum, Griffith University; Paul Hohenlohe, University of Idaho, and Rodrigo Hamede, University of Tasmania

For the past 20 years, an infectious cancer has been killing wild Tasmanian devils, creating a massive challenge for conservationists. But new research, published today in Nature Communications, suggests that devils are evolving rapidly in response to their highly lethal transmissible cancer and that they could ultimately save themselves.

Cancer is usually a disease that arises and dies with its host. In vertebrates, only two known types – Canine Transmissible Venereal Cancer in dogs and Devil Facial Tumour Disease (DFTD) – have taken the extraordinary evolutionary step of becoming transmissible. These cancers can grow not just within their host but can spread to other individuals. Because the cancer cells are all descendants of one mutant cell, the cancer is effectively immortal.

To grow in the new host, the tumour cell must evade detection and rejection by the immune system. Both the devil and dog transmissible cancers have sophisticated mechanisms for hiding from the host’s immune system. Our research suggests that the devil is nevertheless evolving resistance to the disease.

Ecological disaster

The Tasmanian devil is too important to lose – and this would seem careless following the extinction of the thylacine, the world’s largest marsupial predator, in the 1930s. Since the thylacine’s extinction, devils have stepped up to the role of top marsupial predator, keeping numbers of destructive feral cats at bay in Tasmania. With the decline of the devils, invasive species have become more active.

Since it was first detected in northeastern Tasmania in the mid-1990s, DFTD has spread slowly southward and westward. It will reach all parts of Tasmania within a few years; only the far northwest coast and parts of the southwest are still disease-free.

Devil Facial Tumour Disease has spread across the island over two decades.
Menna Jones

Devil populations have declined by at least 80%, and by more than 90% in some areas within six years of local disease outbreak.

DFTD kills most devils at sexual maturity. Before the disease arrived, most devils produced three litters over their lifetime. Most now raise only one.

The cascading effects of the loss of Tasmania’s top predator on the rest of the ecosystem could lead to loss of further species. Already, feral cats have increased activity and small mammals on which cats prey have declined.

Cats may also be preventing recovery of the eastern quoll. Brushtail possums behave as if devils were already extinct, grazing freely on pasture in the open.

Evolution in action

Our research has been a truly international effort. We used data collected by Menna Jones at the University of Tasmania since 1999. This archive of tissue samples now represents one of the best resources globally for studying evolution of an emerging infectious disease in wildlife.

Andrew Storfer at Washington State University and Paul Hohenlohe at the University of Idaho compared the frequency of genes in devils in regions before DFTD arrived to devils 8-16 years after DFTD arrived.

We identified significant changes in two small regions in the DNA samples of devils from regions with DFTD. Five of seven genes in the two regions were related to cancer or immune function in other mammals, suggesting that Tasmanian devils are indeed evolving resistance to DFTD. Evolution is often thought of as a slow process, but these changes have occurred in as few as 4–8 generations of devils since disease outbreak.

Devils are surviving at our long-term sites, despite models that predicted extinction. Previously, studies have shown that devils with lower rates of DFTD showed specific changes in their immune response. Our genetic results might explain why.

New infectious diseases put strong pressure on their hosts to evolve, leading to rapid changes in resistance or tolerance. Rapid evolution requires pre-existing genetic variation. Our results are surprising because Tasmanian devils have low levels of genetic diversity.

Evolution doesn’t just act on the devils; it also also acts on the disease. The disease evolves to not kill the host before it can spread to another host, but also to overcome the host’s defences. Over the long term, pathogen (the cause of the disease) and host usually evolve to live together as rabbits and Myxoma virus have evolved together.

Our results suggest that devils in the wild may save themselves through evolution. However, it is essential for managers to develop strategies that help the devils do so. For example, releasing fully susceptible devils that have had no exposure to the disease into populations where resistance is developing is likely to be counterproductive.

DFTD presents a unique opportunity to study the early stages of the evolution of a new disease and transmissible cancer with its animal host. Ultimately, through future research, we may understand how cancers can become transmissible and how their hosts respond.

The Conversation

Menna Elizabeth Jones, Associate professor, University of Tasmania; Andrew Storfer, Professor & Associate Director, School of Biological Sciences, Washington State University; Hamish McCallum, Professor, Griffith School of Environment and Acting Dean of Research, Griffith Sciences, Griffith University; Paul Hohenlohe, , University of Idaho, and Rodrigo Hamede, Post Doctoral Research Fellow, Conservation Biology and Wildlife Management, University of Tasmania

This article was originally published on The Conversation. Read the original article.

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The link below is to an article reporting on an approval for a mine in the Tarkine region of Tasmania, home to the endangered Tasmanian Devil.

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The link below is to an article reporting on the Tasmanian Devil and a possible vaccine in the near future for the deadly facial tumour disease that is wiping out the species.

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