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BoG Speaker Ties Loss-of-Function Variants in IFIH1 to Severe Pediatric Viral Respiratory Infections

COLD SPRING HARBOR, NY (GenomeWeb) – Loss-of-function variants in the IFIH1 gene predispose children to severe viral respiratory infections, Samira Asgari from the École Polytechnique Fédérale de Lausanne reported at the Biology of Genomes meeting Thursday.

Asgari and her colleagues sequenced the exomes of some 120 children who had to seek treatment at a pediatric intensive care unit following infection with either human respiratory syncytial virus or rhinovirus. By focusing on children with extreme reactions to infections that most people can clear without a doctor's visit, she said her team would be better poised to home in on variants associated with susceptibility to infection. From this, they uncovered rare loss-of-function variants in IFIH1, which encodes a RIG-I-like receptor that's involved in viral RNA sensing.

"We were really excited by this," Asgari said.

Most kids catch a cold before they turn three and most bounce back fairly quickly. Only a tiny percentage — some 1 percent to 2 percent — of kids need to be hospitalized, and, of those, only about 10 percent have to be admitted to the PICU.

Infectious disease, Asgari noted, still represents a large public health problem. She added that 72 percent of pediatric deaths worldwide could be traced to infectious disease and, in the US, pneumonia due to a viral infection accounts for 13 percent of pediatric deaths and some $1 billion in costs.

She and her colleagues prospectively recruited 120 children in Switzerland and Australia who required ventilator support because of a severe respiratory virus infection. Other than this infection, the children were healthy with no known risk factors for disease susceptibility like pre-term birth, chronic disease, or immunosuppression.

They obtained blood samples from the children for exome sequencing. Asgari annotated the variants they uncovered using three different methods and only moved forward with variants concordantly called by all methods.

From this, she and her colleagues identified a handful of rare loss-of-function mutations — with ExAC minor allele frequencies of less than 1 percent — that were enriched within the cohort.

In particular, they uncovered three rare loss-of-function mutations within IFIH1, which encodes a pattern recognition protein that detects long dsRNAs that viruses produce during replication in cells and touches off interferon-β signaling to fight infection.

These three variants were present in eight patients, six of whom were infected with RSV and two of whom had HRV.

The variants included two splicing variants and one stop-gained variant. The splicing variants both lead to exon skipping — though of different exons — and the loss of the C-terminal domain, which is needed for viral recognition. The stop-gained variant, meanwhile, removes part of the helicase domain, which is essential for signaling, Asgari said.

This suggests, she said, that these variants have a functional impact. Through transcriptome profiling, she and her colleagues found that the patients with the splicing variants lost wild-type IFIH1 expression. When they examined the mutated IFIH1 in vitro, they noticed a drop in interferon-beta signaling, suggesting that the variants were unable to induce interferon signaling. The mutated forms further appear to interfere with the function of wild-type IFIH1 when co-expressed.

Mutated IFIH1 further had a shorter half-life than the wild-type version, Asgari said, and when the two were co-expressed, the half-life of the wild-type version also fell. Mutated IFIH1 also lacks ATPase sensitivity. Additionally, in cell-based co-infection studies, Asgari reported that they also observed a dominant negative effect.

Further, they found that both RSV and HRV were restricted in IFIH1-transduced Huh7.5 cells, as compared to wild-type Huh7.5 cells, which lack both IFIH1 and the RIG-I protein. This suggests these variants lead to an immunodeficiency against respiratory RNA viruses.

"Loss-of-function mutations in IFIH1 can explain extreme susceptibility to viral respiratory infection," Asgari added. "Our approach [also shows] the power of extreme phenotype samples … to dissect innate immunity."

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