When a person is infected with a virus, it triggers an immune response that generally results in inflammation. For example – think of the sore throat, redness and swelling that occurs when you are sick with tonsillitis. The immune response is designed to rid the body of the pathogens causing the infection, and sometimes our own cells can be damaged in the process. This is especially true for autoimmune diseases which occur when a person’s immune system attacks healthy cells. Normally, however, the body has mechanisms in place to regulate the immune response to ensure that it does not become dangerous. Fascinated by this process, Dr. Matthew Miller, an Assistant Professor in the Department of Biochemistry and Biomedical Sciences at McMaster University, set out to understand what controlled the body’s response to viral infection.

When studying a group of proteins involved in controlling the immune response at the DNA level, Dr. Miller made an interesting discovery. His work identified a previously unknown function for a protein called senataxin in regulating the immune response. It was clear that senataxin was present in cells to “ensure that our bodies don’t respond inappropriately to infection by mounting a response that is so extreme that it could be dangerous to us.” Mutations in senataxin have been linked to the development of ALS in people under the age of 25 (referred to as juvenile onset ALS) and Dr. Miller’s discovery suggests that infection and inflammation may play an important role in ALS.

The results of his study highlight an interesting paradigm that Dr. Miller feels not many researchers have previously noticed or commented on.
“Many of the genes that are associated with neurological or neurodegenerative diseases have important roles in regulating the immune response,” he says. Dr. Miller recognized that his expertise in viral immunology made him uniquely poised to tackle the problem of determining how inflammation resulting from viral infections may influence neurodegenerative diseases like ALS.

There are two major ways by which viral infections could impact ALS development or progression, according to Dr. Miller. The first is by triggering an immune response. For individuals who have a genetic susceptibility to ALS, triggering of the immune response may set off a neuroinflammatory cascade that could lead to quicker onset or progression of the disease. This doesn’t mean that viral infections will cause ALS – it means that people who were likely to develop ALS anyway due to a genetic link may experience symptoms sooner, or experience faster progression – or both. Inflammation in the brain is particularly dangerous because unlike cells in your arm, for example, that will divide to replace those that die, “neurons typically don’t divide very much, if at all. If we have damage to neurons in the brain, it is really hard to replace those neurons and the effects can be very long-lasting.” The second way is by viruses directly infecting cells and worsening biological pathways that are already problematic in the cells of people living with ALS.

Recent advancements in the field have identified many of these biological pathways that can go wrong in people who have ALS. However, it is not yet known which pathways are the most important for contributing to disease. One way to answer this question is to use viruses as a tool to study the disease.

According to Dr. Miller, “viruses will usually target only select biological pathways, so that can give you a lot of information about which pathway is particularly important for causing ALS.” The strategy of using viruses to gain a better understanding of disease mechanisms has been used in several other scenarios, including cancer, and helps researchers to “understand the particular problems to target in order to come up with new therapies.”

When asked what the next steps were for his research, Dr. Miller explained that he has “experimental evidence that strongly suggests that viral infection can worsen disease” and he is now trying to figure out how and through what pathways. Dr. Miller wants to know if it is the inflammation that is triggered by viral infection or the infection itself that is making disease worsen. He believes by answering this question, “new therapeutic strategies can be developed to either block viral replication itself or block the immune response to see if that has a therapeutic effect in treating ALS.”

Dr. Miller believes that donor support is instrumental in driving research discovery noting that it can be an important alternative to other avenues like government. “When an organization like ALS Canada is able to support research in a particular disease area, it significantly increases the rate at which progress is made as a result.”

You can hear more from Dr. Miller about the role viruses may play in the onset or progression of ALS at the upcoming ALS Canada Virtual Research Forum on August 9th and 10th.

Learn more about the ALS Canada Virtual Research Forum and register to attend.

Posted in: Research