Transcriptômica da Covid-19: identificação de potenciais biomarcadores e mecanismos moleculares da gravidade da doença

Abstract

During the COVID-19 pandemic, transcriptome studies were conducted to investigate potential mechanisms of immune response to SARS-CoV-2 and identify possible treatment targets, virus-host interactions, and disease biomarkers. However, much of this data remains underutilized, and some studies involve a limited number of evaluated patients. This has led to a wide variety of observed results, with few translating into future research or clinically applicable markers. The objective of this study is to identify differentially expressed genes, molecular mechanisms, transcriptional regulators, and potential biomarkers involved in the pathogenesis of severe COVID-19. To achieve this, the methodology was divided into three main approaches: (1) To enhance the identification of molecular targets and biomarkers, this work reviewed the literature on transcriptomics published during the pandemic and its key findings. Specifically, 203 articles reporting transcriptomic experiments conducted on SARS-CoV-2-infected patients and uninfected controls were analyzed. (2) Furthermore, multiple datasets from patients with severe and mild COVID-19 were analyzed in an integrated manner to identify potential targets or pathways associated with disease progression and discover biomarkers of severity. This analysis included three whole blood datasets and one dataset of leukocyte samples. Additionally, data from nasal swabs and peripheral blood mononuclear cells (PBMCs) were examined. (3) Finally, the highlighted genes were evaluated in the serum of patients with mild and severe COVID-19 to validate testable serum biomarkers. The literature highlights the dysregulation of interferon-stimulated genes (ISGs), cytokines, chemokines, and genes related to neutrophil activation. In contrast, integrated reanalysis revealed that patients with severe COVID-19 exhibit overexpression of genes encoding extracellular exosome proteins, endomembrane system proteins, and neutrophil granules. Key targets such as S100A9, LY96, GAPDH, RAB1B, NFKBIA, and CD63 were identified as playing significant roles in the cellular response to infection. Conversely, severe COVID-19 patients show downregulation of genes encoding components of the T-cell receptor complex and nucleolar proteins, including TP53, IL2RB, and NCL. On the other hand, patients with severe COVID-19 present downregulation of genes encoding components of the T-cell receptor complex and nucleolar proteins, including TP53, IL2RB, and NCL. Furthermore, prediction analysis of master regulators—considering the sets of up- and downregulated genes—identified SPI1 as a transcription factor associated with upregulated genes, while TP53, MYC, and MAX were found to play critical roles in regulating the expression of downregulated genes during COVID-19. The validation of testable RNA targets in serum revealed that S100A9, GAPDH, and NFKBIA RNAs are promising biomarkers for assessing the prognosis of severe COVID-19. Notably, several of these genes had not been cited in prior studies, underscoring the novel contributions of this work. These findings offer valuable insights into the molecular pathophysiology of SARS-CoV-2 infection. Additionally, identifying transcriptional factors that regulate the expression of genes involved in infection and the inflammatory response may be pivotal for advancing our understanding of the disease and for the development of new therapeutic targets.