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Background <p>Although pediatric SARS-CoV-2 infection is usually mild; children with chronic conditions are at increased risk of severe disease. Myeloid Cell Leukemia-1 (MCL-1), a key regulator of mitochondrial apoptosis, is expressed as one anti-apoptotic isoform (MCL-1&#xa0;L) and two pro-apoptotic isoforms (MCL-1&#xa0;S and MCL-1ES), but their regulation in pediatric viral infections remains unclear.</p> Methods and results <p>We assessed MCL-1 isoform expression by RT-qPCR and circulating protein levels by ELISA in 324 unvaccinated children (179 SARS-CoV-2-positive and 145 SARS-CoV-2-negative), most with chronic conditions. Statistical analyses included parametric and non-parametric tests, correlation analysis, ROC curves, and multinomial logistic regression. All MCL-1 isoforms were upregulated in respiratory viral infections compared with healthy controls. In contrast, SARS-CoV-2 infection showed attenuated MCL-1 transcript induction, suggesting impaired mitochondrial apoptotic signaling, whereas non-SARS-CoV-2 viruses and coinfections induced robust upregulation. Among SARS-CoV-2-positive patients, MCL-1ES predominated, with increased expression in 95% of subgroups and higher levels in boys, adolescents, and coinfected participants. Chronic conditions, particularly cancer, were major drivers of MCL-1 dysregulation. MCL-1&#xa0;S and MCL-1ES showed good-to-excellent accuracy for predicting mild and moderate disease.</p> Conclusions <p>The proposed MCL-1 isoform ratio including MCL-1ES, strongly predicted disease progression, conferring a 6.5- to 7.6-fold increased risk of critical illness, whereas absence of chronic conditions reduced this risk by 94.8%. In addition to chronic medical conditions, this study identified dysregulated MCL-1 isoform balance as a potential determinant of adverse pediatric SARS-CoV-2 outcomes, and supports mitochondrial apoptosis modulation as a host pathway exploited by SARS-CoV-2 and potentially by other viruses with similar immune evasion strategies.</p>

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Host mitochondrial apoptotic signatures in children with chronic conditions reveal viral modulation of MCL-1 in severe SARS-CoV-2 infection

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月9日

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  • Emilly Henrique dos Santos,
  • Gabriel Acca Barreira,
  • Mariana Okay Saippa,
  • Lucas Augusto Moysés Franco,
  • Mussya Cisotto Rocha,
  • Kelly Aparecida Kanunfre,
  • Maria Fernanda Badue Pereira,
  • Heloisa Helena Sousa Marques,
  • Thelma Suely Okay

摘要

Background

Although pediatric SARS-CoV-2 infection is usually mild; children with chronic conditions are at increased risk of severe disease. Myeloid Cell Leukemia-1 (MCL-1), a key regulator of mitochondrial apoptosis, is expressed as one anti-apoptotic isoform (MCL-1 L) and two pro-apoptotic isoforms (MCL-1 S and MCL-1ES), but their regulation in pediatric viral infections remains unclear.

Methods and results

We assessed MCL-1 isoform expression by RT-qPCR and circulating protein levels by ELISA in 324 unvaccinated children (179 SARS-CoV-2-positive and 145 SARS-CoV-2-negative), most with chronic conditions. Statistical analyses included parametric and non-parametric tests, correlation analysis, ROC curves, and multinomial logistic regression. All MCL-1 isoforms were upregulated in respiratory viral infections compared with healthy controls. In contrast, SARS-CoV-2 infection showed attenuated MCL-1 transcript induction, suggesting impaired mitochondrial apoptotic signaling, whereas non-SARS-CoV-2 viruses and coinfections induced robust upregulation. Among SARS-CoV-2-positive patients, MCL-1ES predominated, with increased expression in 95% of subgroups and higher levels in boys, adolescents, and coinfected participants. Chronic conditions, particularly cancer, were major drivers of MCL-1 dysregulation. MCL-1 S and MCL-1ES showed good-to-excellent accuracy for predicting mild and moderate disease.

Conclusions

The proposed MCL-1 isoform ratio including MCL-1ES, strongly predicted disease progression, conferring a 6.5- to 7.6-fold increased risk of critical illness, whereas absence of chronic conditions reduced this risk by 94.8%. In addition to chronic medical conditions, this study identified dysregulated MCL-1 isoform balance as a potential determinant of adverse pediatric SARS-CoV-2 outcomes, and supports mitochondrial apoptosis modulation as a host pathway exploited by SARS-CoV-2 and potentially by other viruses with similar immune evasion strategies.