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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月1日

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  • 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 Eltaras,
  • Malak W. ElBenhawi,
  • Jantan Dawa,
  • Marwa S. Hamza,
  • Riem M. El-Messiery,
  • Mohamed El Ansary,
  • Engy A. Abdel-Rahman,
  • Sameh S. Ali

摘要

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.