What is it about?
Severe COVID-19 turns neutrophils—usually protective—into harmful cells. We discovered that PCNA, a cytoplasmic protein a with a deeply conserved, hexagonal ring structure, assembles a dangerous molecular scaffold (with partners like calprotectin) that reprograms neutrophils to attack the body. Targeting this hub could stop the damage.
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Why is it important?
Beyond COVID-19, this work challenges the dogma of neutrophils as rigid effectors. PCNA’s cytoplasmic dominance redefines their adaptability—and offers a precision target to curb inflammation without global immunosuppression. With existing inhibitors like T2AA already showing preclinical efficacy, the path from mechanism to medicine feels tangibly close.
Perspectives
This study reflects the passion and synergy of an international consortium united by a shared obsession: decoding neutrophil plasticity in disease. While cytosolic PCNA has long been overlooked—eclipsed by its nuclear fame—our collaborative data cement its role as a central reprogramming hub in COVID-19 pathogenesis. By showing how PCNA hijacks calprotectin to assemble a pro-inflammatory scaffold, we reveal a druggable vulnerability in hyperactive neutrophils. I’m deeply grateful to my colleagues for turning curiosity into actionable science. If neutrophils are the storm in severe disease, PCNA may well be the lightning rod and we’re just beginning to harness its potential.
Veronique WITKO-SARSAT
Read the Original
This page is a summary of: Cytosolic proliferating cell nuclear antigen (PCNA) orchestrates neutrophil hyperactivation in COVID-19, Proceedings of the National Academy of Sciences, October 2025, Proceedings of the National Academy of Sciences,
DOI: 10.1073/pnas.2503667122.
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