Mouse research explains influenza's connection to brain disorders

For years, there’s been a puzzling hint found in medical records that catching influenza in the middle of a woman’s pregnancy might increase the risk that her child will develop schizophrenia as a young adult. Now scientists are starting to understand how such a connection might work. Research in mice, by Dr. Paul Patterson of the California Institute for Technology, points to our own immune systems, not the virus, as the culprit.

Dr. Patterson, who explores how the immune system functions within the brain, presented his findings at an international conference in Australia last week. His team also found a connection to between influenza and autism. The mice with schizophrenic characteristics also showed a brain difference common in autism, the loss of a specific type of brain cells called Purkinje cells.

Common disorders of the developing brain

About 1% of the population in Canada suffers from schizophrenia. This brain disease is one of the most serious mental illnesses. Common symptoms are mixed-up thoughts, delusions, hallucinations, and bizarre behaviour. The symptoms often don’t become noticeable until late adolescence or young adulthood.

Perhaps as many as six children per thousand have a disorder in the autistic spectrum. This biologically-based disability shows up in the first few years of life. Neither disorder has a single simple cause. Both are thought to be triggered by environmental influences in children with a genetic predisposition. There may be a dozen or more genes that can each increase the chance that a child will develop autism or schizophrenia. But genes are clearly not the whole story. Even identical twins have different outcomes about half the time.

For about two decades, researchers have grappled with the suggestion that seasonal flu, influenza epidemics, and other viral and bacterial infections may harm the developing brain of an embryo in subtle ways. Based on early studies, mental health organizations already suggest that pregnant women try to avoid infection. “Prevention is mainly common sense,” Dr. Patterson says, “but we often don’t do it because we just expect to get a cold or the flu.”

Evidence from epidemiology

Since 1988, researchers have tried to understand the excess of babies born around five months after a flu epidemic who go on to develop schizophrenia. In 2000, health researchers trying to confirm a connection between flu and schizophrenia were given permission to study blood samples from 19,000 women who had given birth between 1959 and 1967. Antibodies to the flu virus revealed which women had fought the infection during their pregnancies. By following up with the children, it was clear that they were at increased risk of developing schizophrenia. While 1% of the general population becomes schizophrenic, almost 7% the flu-affected children developed the disease. The strength of this influence is similar to rubella, a maternal infection well known to increase the child’s the risk of schizophrenia. Most people are now vaccinated against rubella in childhood.

It is worth noticing that the majority of the children in this study who grew up to have schizophrenia were not affected by flu while in the womb. The disorder has many causes.

Dr. Catherine Schaefer, an epidemiologist with Kaiser Permanente, studies the causes of schizophrenia and was a co-author of the antibody study. According to Dr. Schaefer, “the development of brain imaging technology has allowed us to see consistent structural differences in the brains of some people with schizophrenia. The nature of these differences suggests that the insult must have occurred before the child was even born. That tells us we have to look for things that affect the mother, like toxic exposure, nutritional deficiencies, hormonal problems, and infection.” Dr. Schaefer says that research into each of these possibilities should continue.

An inflammatory signal

Human children could not help answer these questions about prenatal infections. But in mice, Dr. Patterson found that the brain disturbances similar to schizophrenia and autism occurred if he gave mid-pregnancy mice a common flu virus. Even when he replaced the virus with non-infectious synthetic genetic material, the offspring showed the same behavioural and physical differences.  Using this decoy “infection” allowed him to remove the virus from the picture and focus on the immune response. Mouse fetuses infected in last third of the pregnancy turned out fine, as also observed in the human flu epidemic studies.

In Dr. Patterson’s experiments, a chemical signal called interleukin-6 (IL-6) seemed to be responsible for harm to the embryo’s brain. IL-6, which is produced in a normal cellular response to injury, is also known to trigger damage to the brain tissues that can occur during infections.

Dr. Patterson injected his synthetic virus decoys into mother mice engineered to lack the IL-6 gene. The IL-6 signal was not produced, and the mice had normal pups. The team at CalTech was also able to rescue the pups by injecting a specific antibody to IL-6 along with the fake virus. The antibody chemically tangles up the interleukin-6 signal. This principle is already used in antibody therapies to calm the self-destructive immune systems of patients with severe Crohn’s disease and rheumatoid arthritis.

The future may hold therapies designed specifically to ease the immune system’s furor. A lot of scientific research is currently focused on inflammation and the web of signals that produce this response. But Dr. Patterson is sceptical about this approach, pointing to the risks involved in testing new drugs on pregnant women and their babies.

Instead, he hopes there will be a way to intervene later in children showing early signs of autism or schizophrenia. “Cytokines in the brain can alter your mental state,” Dr. Patterson says, “and with enough understanding of the immune system, we may be able to help infants, children, or perhaps even adults with these serious disorders.”

For now, prevention may be the best option. If you’re a healthy woman planning to get pregnant, take these precautions:

• make sure you get enough rest and eat a balanced diet to keep your immune system in good shape
• teach your children good respiratory manners: cough into a tissue or hand, not Mum’s face
• avoid people who have influenza if you can
• wash your hands frequently, especially during flu season
• get a flu shot each fall

A case of the sniffles is no reason to panic. Further research is needed to confirm the connection between a pregnant woman’s immune response and her child’s brain. Still, prevention is cheap, easily available, and can be quite effective in reducing your exposure to influenza.

Resources:

Here comes the flu season again!

http://www.autismsocietycanada.ca

http://www.schizophrenia.ca/