Role of human airway epithelial cell death in the inflammation caused by 2019-nCoV and confirmation by transcriptional analysis of infected patients

Abstract

2019-nCoV infection results in pneumonia marked by intense inflammation. There is still no specific treatment for COVID-19 disease. The fact that 2019-nCoV infection causes intense pathological inflammation shows that surviving the infection is more a matter of tolerating lung damage (damage tolerance) than properly controlling the load viral (pathogen tolerance). New perspectives for the treatment of pneumonia involve host-directed therapies, and should include therapeutic strategies aimed at damage tolerance mechanisms. Lung damage in 2019-nCoV infection involves the destruction of pulmonary alveoli as a result of the death of infected alveolar epithelial cells, and the cytokine storm. Comorbidities, such as chronic lung diseases, obesity, hypertension, cardiovascular diseases, among others, aggravate the infection caused by the new coronavirus. This project has three well-defined objectives: i. to study the role of the death of human alveolar epithelial cells infected by 2019-nCoV, as direct mediators of macrophage activation; ii. analyze the transcriptome of patients with or without comorbidities in order to relate the findings in vivo and in vitro; iii. to establish correlations between transcripts and comorbidities. These objectives are in line with the objectives of the Thematic Project under my coordination, aiming at investigating mechanisms that exacerbate asthma and acute bacterial pneumonia, and diabetes and tuberculosis comorbidity. At the end of the project's development, our purpose will be to list molecular targets to be investigated as pharmacological agonists or antagonists in immunotherapies directed to the host with COVID-19 with or without comorbidities, aiming at tolerance to the damage. This project is a multicentre proposal, which results from the collaboration among FMRP-USP, FCFRP-USP and Hospital São Paulo de Ribeirão Preto, in a collective effort to better understand the immunopathology associated with COVID-19. The peripheral blood samples from patients and individuals from the control group will be shared to carry out different methodologies and the data collected will also be shared, featuring robust research and strengthening links of scientific collaboration. (AU)