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Disruption of neutrophil homeostasis is associated with functional alterations in mitochondria of critically ill COVID−19 patients

Article scientifique 2026 Anglais

Résumé

Understanding the molecular mechanisms underlying neutrophil dynamics during COVID−19 disease progression is essential for managing severe inflammatory conditions. We investigated whether alterations in neutrophil mitochondrial function and calcium handling are associated with disrupted neutrophil homeostasis in critically ill COVID−19 patients. We analyzed neutrophil counts, phenotypes, and apoptotic profiles in critically ill COVID−19 survivors (ICU-S) and non-survivors (ICU-NS) compared with healthy controls. Flow cytometry, metabolic profiling, immunofluorescence imaging, and small RNA sequencing (miRNA-seq) were used to characterize neutrophil apoptosis-related pathways and mitochondrial function in freshly isolated neutrophils. Critically ill COVID−19 patients showed marked neutrophilia and a higher proportion of immature CD16low neutrophils relative to controls. Both ICU-S and ICU-NS groups exhibited reduced neutrophil apoptosis, as evidenced by fewer annexin V+ cells and lower cleaved caspase−3 signal compared with healthy controls. Although exploratory miRNA-seq in a small subset of ICU patients identified differentially expressed miRNAs with predicted enrichment in apoptosis- and calcium-related pathways, these mortality-associated miRNA signatures were not corroborated by functional apoptosis readouts (cleaved caspase−3 and annexin V) between ICU-S and ICU-NS. Neutrophils from ICU patients also demonstrated altered calcium handling, hyperpolarized mitochondrial membrane potential, increased complex II–linked respiration, and elevated mitochondrial ROS relative to controls. Neutrophils from critically ill COVID−19 patients display coordinated alterations in calcium handling, mitochondrial activity, and apoptosis consistent with impaired neutrophil clearance and disrupted homeostasis. These findings are observational and do not establish causality; the miRNA results should be interpreted as hypothesis-generating rather than validated mortality biomarkers.

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Elkhodiry, A., Yasseen, B., El-sayed, H., Zidan, M., Kamel, A., Hamdy, R., Gohar, S., Badawy, M., Saber, A., El-Shqnqery, H., Samir, O., Sayed, A., Eltaher, A., Abdelkhalek, H., Eltaras, M., Elbenhawi, M., Dawa, J., Hamza, M., El-Messiery, R., Ansary, M., Abdel‐Rahman, E., Ali, S. (2026). Disruption of neutrophil homeostasis is associated with functional alterations in mitochondria of critically ill COVID−19 patients. https://doi.org/10.1038/s41598-026-38741-y

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Auteur(s)

Aya A. Elkhodiry Basma A. Yasseen Hajar El-sayed Mona Zidan Azza G. Kamel Rehab Hamdy Sara Gohar Mohamed A. Badawy Aya Saber Hend E. El-Shqnqery Omar Samir Ahmed A. Sayed Ashraf Eltaher Hadeer Abdelkhalek Mennatullah Mohamed Eltaras Malak W. Elbenhawi Jantan Dawa Marwa S. Hamza Riem M. El-Messiery Mohamed El Ansary Engy A. Abdel‐Rahman Sameh S. Ali

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