ZBP1 links interferon treatment and dangerous inflammatory cell death during COVID-19

Scientists from St. Jude Children’s Research Hospital have shown that the innate immune sensor, ZBP1, and its associated inflammatory cell death pathway, PANoptosis, are major contributors to the negative effects of interferon treatment and high interferon levels in some COVID-19 patients. The work was published today in Science Immunology.

Interferon therapy is a proposed treatment for viral infections that should help the immune system efficiently clear viruses. But in patients with established SARS-CoV-2 infections, interferon therapy has produced mixed results, in some cases even increasing mortality, which appears to be mediated by ZBP1.

“Our study improves our fundamental understanding of innate immunity and inflammatory cell death pathways and shows how modulating these processes during coronavirus infection could be used to improve patient outcomes,” said corresponding author Thirumala-Devi Kanneganti, Ph.D., St. Jude Department of Immunology vice-chair.

“Interferons induce the expression of interferon-stimulated genes. Some of these genes show antiviral function while some drive cell death,” she said. “One such interferon-stimulated gene is ZBP1. Interferon induces robust expression of ZBP1, which can then sense SARS-CoV-2 and drive inflammatory cell death. This cell death is detrimental for patient outcomes.”

Screening for a gene

The scientists wanted to find out which genes sensed SARS-CoV-2 and contributed the most to poor outcomes in COVID-19 patients treated with interferon. To find these genes, they used a CRISPR-Cas9 screen that knocked out genes in macrophages infected with coronavirus. Researchers then observed which genes were missing in the surviving cells. These genes were likely critical for sensing the virus and driving cell death, since their deletion resulted in the cells surviving the infection. This unbiased screening method identified Zbp1 as one such gene. ZBP1 was also expressed at higher levels in the immune cells of patients with worse outcomes during COVID-19 than those who fully recovered.

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