Extreme an infection might elevate odds of autism in some kids | Spectrum
Early Disease: Autistic boys were more likely than their non-autistic peers to have a serious infection before age 4.
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Serious infections in early childhood have been linked to autism – at least in some boys, a new study in mice and humans suggests. The results were published today in Science Advances.
Researchers analyzed the health records of millions of children in the United States and found that boys diagnosed with autism were more likely to have an infection than non-autistic boys aged one and a half to four years old who required medical treatment.
The study also showed that eliciting a strong immune response in newborn mice with only one copy of TSC2, a gene associated with autism, leads to social memory problems in adult male rodents. In humans, mutations in TSC2 cause tuberous sclerosis, a disease characterized by non-cancerous tumors and skin growths. About half of all people with tuberous sclerosis also have autism.
“If the TSC2 mutation were enough to cause autism, anyone with that mutation would have autism – but they don’t,” says Alcino Silva, senior researcher, director of the Integrative Center for Learning and Memory at the University of California. Los Angeles .
Previous studies show that children with severe infections in the child or their mother are more likely to develop autism, but not all children with severe infections are diagnosed with autism.
The new study is the first to look at the link between immune activation and a specific genetic variant associated with autism, says Silva. The results suggest that genetics and severe infections represent a “two-hit” scenario for autism.
The work also highlights the importance of vaccinating children, says Manuel López Aranda, a postdoctoral fellow in Silva’s laboratory.
“If it is true that serious infections predispose children to neuropsychiatric disorders, the best way to avoid serious infections in children is to vaccinate them,” he says.
Immune activation:
Silva, López Aranda, and their colleagues injected newborn mice that were missing a copy of TSC2 with a compound that mimics a viral infection. When isolated from their mothers, the pups squeaked with shorter and simpler calling sequences than control pups, the researchers found. This simplified call repertoire can be associated with early social communication difficulties in people with autism.
As adults, the male TSC2 mice seemed to have difficulty recognizing and remembering other mice: they did not show the typical fondness for spending time with a mouse they had never seen before, but they did pull a novel object a familiar.
An analysis of gene expression in three brain areas involved in social behavior indicated that the male TSC2 mice injected with the viral mimic had increased levels of an immune molecule called interferon, which immune cells use to fight off viruses, compared to controls release. The injection also activated microglia, immune cells in the brain that produce interferon and help form neural connections.
Gender differences in the number and function of microglia could explain why immune activation only led to problems with social memory in male TSC2 mice, says López Aranda. The result is consistent with the observation that autism is about four times more common in boys than in girls.
Breaking down microglia or clearing the receptors for interferon saved the animals’ social memory problems. Giving the mice a drug called rapamycin, which is being tested to treat tuberous sclerosis, counteracted their strong immune activation and also alleviated their social memory problems. Rapamycin works by suppressing mTOR, a signaling pathway that is overactive in tuberous sclerosis and in response to viral infections.
To investigate whether immune activation in early childhood could be linked to social and other behavioral problems in humans, the researchers examined the insurance claims of more than 3.5 million children in the United States. Of these, 4,417 girls and 18,232 boys were diagnosed with autism. The researchers found that autistic boys were 40 percent more likely to develop an infection that required medical treatment by age one and a half to four years.
Model with two hits:
Many researchers have long focused on genetic or environmental factors that could contribute to autism. If you look at how the two work together, the new study is “a breath of fresh air,” says Mauro Costa-Mattioli, a professor of neuroscience at Baylor College of Medicine in Houston, Texas, who was not involved in the research.
The results of the animal studies provide a mechanism by which the immune response to a viral infection could lead to some autism-like characteristics, says Costa-Mattioli. However, he warns that analyzing medical records only reveals a link between a severe infection and the diagnosis of autism. This doesn’t mean the viral infection is causing the behavioral disorders associated with autism, he says.
It’s also possible that the boys who contracted a serious infection and who were diagnosed with autism have genetic mutations associated with autism, says Eric Klann, director of the Center for Neural Science at New York University. who was not involved in the study. If that were true, says Klann, it would support the “two-hit” hypothesis that the interaction between genes and the environment can increase the risk of autism.
The work could also have clinical implications, as it suggests rapamycin mitigates the deleterious effects of strong immune activation on social skills, Silva says.
“Of course this has to be tested and demonstrated on humans,” he says, “but our work suggests that it might just be possible.”
Quote this article: https://doi.org/10.53053/MQUR6777
