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Too Much of a Good Thing

Credit: Petr Ciz/Adobe

Credit: Petr Ciz/Adobe

By Claire L. Thompson & Markus J. Hofer

Our immune system protects us from disease but can also cause harm. Sydney scientists are now trying to interfere with the immune signals that can provoke serious side-effects.

The symptoms are all too familiar: pounding headache, scratchy throat, achy muscles and a rising fever. What you are likely experiencing are the hallmarks of a viral infection such as the common cold.

Ironically, these symptoms are often a consequence of your body’s immune response rather than the virus itself. As you fight off the infection, the very defence system that is designed to protect you can become the reason you feel so miserable.

The immune system must strike a delicate balance when it comes to viral infections. An insufficient response and the virus will persist as a chronic infection or kill the host. An over­reaction can be too much of a good thing, damaging the body and potentially causing death.

So how does the immune system fine tune its response to viruses? And can we use this knowledge to fight viral infections more effectively or even to treat diseases caused by an over­active immune response?

Lessons from the Immune System

Over the course of human evolution, viruses have been our constant companions. They are deceptively simple, comprised of nucleic acids protected by a coat of proteins.

However, our bodies have evolved complex strategies to deal with viruses. Once our body detects a virus, most of our cells have the capacity to secrete a family of proteins known as type I interferons. As their name suggests, interferons interfere with viral replication, preventing the virus from spreading. They issue a call to arms to the rest of the immune system to come and defeat the virus.

However, interferons also play an important role in fine tuning the immune system, acting as a master regulator to ensure the immune response does not overwhelm the body.

Type I interferons are produced by cells in response to a virus, and this usually happens very quickly – within minutes to hours. Once type I interferon is released by a cell, it can interact with a specific receptor on the surface of many different types of cells. When interferon activates this receptor, a cascade of reactions occurs.

This process, termed type I interferon signalling, relies on three central molecules known as STAT1, STAT2 and IRF9. These molecules are gatekeepers, controlling how the cell responds to interferon. After these molecules are activated by type I interferon, they form a complex that moves into the cell’s nucleus and stimulates the expression of large numbers of genes that inhibit viral proteins, activate immune cells and produce chemicals that put the body into a state of alert.

Our team is trying to find out how STAT1, STAT2 and IRF9 control our immune response. We are particularly interested in how these gatekeepers work in the brain. Arguably the most complex and delicate organ in the human body, the brain contains over 100 billion nerve cells that, when damaged, have a very limited ability to repair themselves. Viral infections as well as the host’s own immune response can irreversibly damage the brain.

To protect the brain, it is separated from the rest of the body by a special security system known as the blood–brain barrier. One of the roles of the blood–brain barrier is to prevent viruses from reaching the brain. However, some viruses are able to sneak through and cause infection.

The brain is therefore a good system to study interferon signalling, as viral infection represents a unique challenge where the brain’s immune system has to not only control the infection but also protect the easily damaged tissue. Type I interferons play a critical role in maintaining this balance.

Interfering with Type I Interferon Signalling

Type I interferons are key defence mechanisms during infection of the brain, and interferon signalling is therefore tightly regulated. In order to understand how type I interferons are controlled, we are using mice that are missing genes for each of the three signalling molecules.

To test the role of each of these molecules, we exposed the mice to a virus called lymphocytic choriomeningitis virus (LCMV). LCMV is carried primarily by mice, but cases of human infection have been reported in Australia, Europe, America and Japan. In humans, it usually does not cause disease except in people with suppressed immune function, such as AIDS patients and transplant recipients.

The reason why LCMV is so useful as a laboratory model is that it does not actually kill the host cells. Instead, disease is caused by the immune system itself.

In mice, LCMV is capable of causing encephalitis, where both the brain and the meninges – the membrane that surrounds the brain – become inflamed. Mice with a fully functioning immune system are unable to eliminate the virus, and develop a lethal encephalitis.

A group of immune cells called CD8+ T cells play a key role in this disease. CD8+ T cells are also known as killer T cells. Their role is to kill virus-infected, cancerous or otherwise damaged cells. They do this by releasing toxins that punch holes in the cell wall. This results in cell death, and can lead to extensive tissue damage and organ destruction.

So what happens when you remove the gatekeepers – STAT1, STAT2 and IRF9 – and impair interferon signalling? Curiously, mice that lack the gene for IRF9 or STAT2 are not killed by LCMV. Instead, these mice are unable to get rid of the infection, with the virus persisting at low levels in the brain, accompanied by a chronic immune response. In contrast, mice that lack the signalling molecule STAT1 die from LCMV infection.

However, the death of these mice is not mediated by CD8+ T cells but the consequence of overactive CD4+ T cells. These cells are also called helper T cells, and have important roles in regulating the activity of immune cells during infection.

This shows us that STAT1, STAT2 and IRF9 play vastly different roles in interferon signalling.

Towards Treatment

Understanding how interferon signalling regulates the immune response will open new possibilities for treating disease. Interferons are increasingly recognised as a cause of neurological diseases. Cerebral interferonopathies are a group of debilitating neurological disorders that all feature chronic production of type I interferon in the brain. They include genetic disorders such as Aicardi-Goutières syndrome and autoimmune diseases such systemic lupus erythematosus. Too much type I interferon is also thought to contribute to dementia in people infected with HIV.

Interferonopathies have no known cure, and treatment is often more about managing symptoms rather than targeting their cause. Altering interferon signalling in these diseases might lead to new, more effective therapies.

Type I interferon is also used as a drug to treat several diseases, including multiple sclerosis. For some of these diseases, interferon remains the only treatment available. However, its use has been limited because of the side-effects it causes, ranging from flu-like symptoms to seizures, confusion and coma.

The reason that interferon can cause such severe side-effects is because interferon signalling involves a tangle of different pathways that switch on hundreds of different genes. Some of these genes protect against viral infection, but others lead to the severe side-effects.

By understanding the pathways involved in interferon signalling, we may be able to reduce its side-effects and make interferon more tolerable as a treatment.


Claire L. Thompson was previously an honorary research fellow of The University of Sydney. Markus J. Hofer is a senior lecturer for molecular biology and genetics at The University of Sydney.