Abstract
COVID-19 is a multi-system disease that affects not only the respiratory system but also the neurological, hematological, and immune cells and tissues. The understanding of how the virus infiltrates and impacts a diverse set of human cells is still incomplete. This work examined bulk RNA-seq data from recovered COVID-19 patients (COVID-19 survivors with or without post-acute complications) to uncover the persisting perturbations in biological pathways. The investigation also analyzed the transcriptomic signatures in the lungs and brain tissues of deceased patients during the acute phase of infection to understand COVID-19 impact on these organs. In recovered COVID-19 patients, the severity of acute COVID-19 influenced the subsequent disturbance of gene expression patterns in the post-acute disease phase. Gene expression patterns in the lungs and brain tissues of deceased COVID-19 patients correlate with the diverse pulmonary and neurological symptoms observed in these patients. We have detected significant alterations in the expression of mitochondrial genes, such as COX7C, COX7A2, ATP5PO, ATP5F1C and NDUFB8, which reflect a compensatory upregulation in response to viral suppression of mitochondrial function. This COVID-19 induced response persists up to 24 weeks post-infection, suggesting a sustained effort of the host to mitigate mitochondrial dysfunction. Additionally, in critical and severe COVID-19 cases, gradual upregulation of UBE3A expression was detected, which previously has been linked to favorable COVID-19 outcomes. Long-term anosmia related SHH gene was upregulated in recovered critically-ill COVID-19 patients. IL6 emerged as a central hub gene consistently expressed in both lung and brain tissues of deceased COVID-19 patients, underscoring its role in driving the inflammatory pathophysiology of COVID-19 within these organs. Collectively, our study emphasizes IL6 as a central cytokine driving the inflammatory response in both lung and brain tissues, and demonstrates the virus's capacity to induce long-lasting changes in nuclear-encoded mitochondrial gene expression in the blood of recovered patients. Our findings have significant implications for developing targeted interventions for post-COVID-sequelae. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-025-00450-1.