Systemic and integrative analysis of T lymphocyte exhaustion mechanisms in patients with COVID-19

Abstract

The current pandemic of the Coronavirus Respiratory Disease 2019 (COVID-19) represents a state of international public emergency. The virus causing the disease is called Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and has been circulating throughout the world, triggering clinical manifestations ranging from asymptomatic cases to severe acute respiratory syndrome and death, especially of individuals with comorbidities (ex: hypertension, Asthma, and Diabetes). Thus, suggesting the influence of immunological and other host factors in controlling the development of the disease. Meanwhile, patients who develop severe illness may die due to intense immune dysregulation. However, the knowledge about the systemic immunological mechanisms that control the protection against SARS-CoV-2 is still scarce and the systemic aspects of the immune response of T lymphocytes, effector leukocytes and immune system regulators, remain to be characterized. The hypothesis of this project is that a possible predisposition to systemic exhaustion profile of T lymphocytes, i.e. the interaction network of genes/proteins associated with mechanisms of exhaustion, has relevant relationships with different ontogenetic categories dysregulated in COVID-19, influencing the severity of the disease phenotype. Thus, this project aims characterize the mechanisms of exhaustion of the immune response of T lymphocytes from patients infected with SARS-Cov-2, with mild and severe COVID-19. We will carry out a systemic and integrative approach, investigating the transcriptome of T CD4+ lymphocytes, followed by specific functional assays to validate the high-throughput screening (transcriptome analysis). In addition, we will perform a meta-analysis of data previously uploaded to ArrayExpress and GEO (Gene Expression Omnibus) to determine the networks of gene co-expression that systemically regulate the immune response to SARS-CoV-2. This high-throughput approach analysis will allow us to define the immunological signatures, signaling pathways and networks of gene co-expression and the molecular (interactome) and metabolic (metabolome) interactions involved in the immune response against SARS-CoV-2. Then, will promote a translational and multidisciplinary study that can identify biomarkers for the differential diagnosis. This fact will pave the way for the development of new specific therapies that reduce mortality and morbidity induced by the virus. (AU)