Role of fat in rare neurological disorder and viral infections

A mutation in a protein regulating natural killer (NK) cells’ function is at the root of immune deficiency in some people with a rare genetic condition characterized by cognitive and developmental delay, seizures, and other manifestations, new research suggests.

The researchers found that loss or mutations in a gene called MEF2C disrupted the ability of NK cells to take up chemical compounds called lipids that are used to fuel crucial functions such as tumor cell killing and creating inflammatory molecules. They found that people with the rare neurological syndrome called (MCHS) who have the mutation in this gene are particularly vulnerable to viral infections.

The findings, published  in Nature Immunology, are the first to observe that these people are immune deficient and point to lipid supplementation with oleic acid as a potential therapy.

“Human NK cell deficiencies are rare but lead to a dramatic increase in vulnerability to viral infections,” said the first author. “Clinically, we still don’t know a lot of genes that can result in NK cell deficiency when mutated. Our findings identify NK cell defects associated with MEF2C haploinsufficiency syndrome that might explain the frequent infections that some of these patients experience.

“Knowing that these patients might have impaired immune systems can improve how we take care of them,” the author added.

Using CRISPR gene editing, the researchers screened 31 genes in human NK cells and found that MEF2C was a crucial driver for multiple functions in those cells. They also found that oleic acid enhanced the protective activity in cells from MEF2C haploinsufficient people and normal NK cells.

The findings also have broader implications for immunity and cell therapies, the author said.

“Harnessing lipid metabolism to engineer better NK cell therapies may have promise in the realm of cancer immunotherapy, as previous studies have found that tumor-infiltrating immune cells can become metabolically impaired,” the author said. “In the realm of NK cell immunodeficiencies, we have noted a trend that multiple neurodevelopment disorders seem to be accompanied by NK cell defects.”