Molecular biology reports · 2026
Host mitochondrial apoptotic signatures in children with chronic conditions reveal viral modulation of MCL-1 in severe SARS-CoV-2 infection.
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Dos Santos Emilly Henrique, Barreira Gabriel Acca, Saippa Mariana Okay, Franco Lucas Augusto Moysés, Rocha Mussya Cisotto, Kanunfre Kelly Aparecida, Pereira Maria Fernanda Badue, Marques Heloisa Helena Sousa, Okay Thelma Suely
Аннотация
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.
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.