In a study reported on Frontiers in Immunology, Brazilian researchers from Sao Paolo University have taken the first steps toward understanding why some people are naturally resistant to SARS-CoV-2 infection. The results suggest that certain genetic variants found more frequently in resistant subjects are associated with more efficient activation of natural killers (NKs).
“Our hypothesis is that the genomic variants most frequently found in the susceptible spouse lead to the production of molecules that inhibit activation of NKs. However, this theory has yet to be validated by means of functional studies,” Mayana Zatz, last author of the paper.
According to Zatz, the fact that resistance to SARS-CoV-2 is a relatively common trait in the population—unlike resistance to HIV, the virus that causes AIDS, for example—points to a complex genetic inheritance in which many genes are involved. “That means that to find something significant when we look at the genome as a whole we would need to have a huge sample with more than 20,000 volunteers. So we decided to focus on two large groups of genes associated with the immune response: the main histocompatibility complex [MHC] and the leukocyte receptor complex [LRC],” Zatz explained. “MHC genes determine whether two individuals are compatible in the case of a transplant, for example.”
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Analyzing the MHC, they found that variants of the genesMICAandMICBappeared to influence resistance to SARS-CoV-2. "In the case ofMICA, the most frequent polymorphism in infected subjects appears to increase production of the protein encoded by this gene, possibly in soluble form, inhibiting activation of NK cells,” he said. “In the case ofMICB, a variant associated with reduced expression of the messenger RNA that encodes the NK-activating protein was 2.5 times more frequent among susceptible subjects. Both pathways, therefore, lead to lower activation of this immune system barrier.”