Validation and derivation of serum microRNA panel as biomarkers of COVID-19 severe forms

Abstract

Coronavirus disease 2019 (COVID-19) is an acute respiratory infection caused by the severe acute respiratory syndrome coronavirus - 2 (SARS-CoV-2). Approximately 80% of patients with COVID-19 have mild to moderate symptoms, 13.8% have severe disease (dyspnea, tachypnea, and hypoxia) and 6.1% develop critical symptoms (respiratory failure, septic shock or multiple organ dysfunction). The lethality of COVID-19 is around 4%. Severe symptoms manifest after approximately 7 to 8 days from the beginning of the disease, and progression to the critical form occurs on average after the 11th day of symptoms. The pathogenesis of COVID-19 is probably related to the invasion of SARS-CoV-2 in the lung epithelial cells combined with the host's immune reaction. The uncontrolled systemic inflammatory response, resulting from the release of large amounts of pro-inflammatory cytokines, is the main mechanism behind severe acute respiratory syndrome and multiple organ failure, the two main causes of death in COVID-19. The mechanisms of interaction between SARS-CoV-2 and the host cell, and the factors associated with progression to critical COVID-19 are not known. Epigenetic mechanisms, such as gene expression regulation by microRNAs (miRNAs,) may be at the basis of the immunological changes associated with COVID-19. Therefore, the main objective of the study is to identify a panel of circulating miRNAs from the host capable of forming a biomarker of critical COVID-19 risk and death risk. To do this, we will select two cohorts of patients hospitalized for COVID-19. The first cohort, composed of 20 patients, is for the derivation of miRNAs differentially expressed in patients with critical symptoms and the second cohort, composed of 100 patients, is for validating the profile of miRNAs associated with critical COVID-19. Both cohorts will be tested in 2 moments: admission and 4th day of hospitalization or the day the patient present with critical symptoms. The screening of miRNAs differentially expressed in critical COVID-19 will be done by miRNA-Seq technique and the validation of miRNAs by RT-qPCR. For the construction of a miRNA panel (signature) we will use multiple logistic regression analysis. Potential signaling pathways and biological processes associated with validated miRNAs that are relevant to the pathogenesis of COVID-19 will also be identified. The identification of miRNAs associated with critical COVID-19 risk and their possible pathways of action will contribute to the identification of cases with a higher risk of fatal outcome and to better understand the disease pathogenesis. In addition, it will facilitate the development of new therapeutic strategies based on silencing genes with pathological effects. (AU)