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

The current pandemic of the new respiratory disease Coronavirus 2019 (COVID-19) represents a state of international public emergency. The virus that causes the disease is called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has been circulating all over the world, triggering clinical manifestations ranging from asymptomatic cases to severe acute respiratory syndrome and death, especially of individuals with comorbidities (eg hypertension, diabetes and asthma). Thus, it is suggested the influence of immunological factors and other intrinsic factors of the host in controlling the development of the disease. Meanwhile, patients who develop severe illness may die due to intense immunodegulation. Yet, the knowledge about the systemic immunological mechanisms that control protection against SARS-CoV-2 is still scarce and the systemic response of CD4 + T lymphocytes, effector leukocytes and regulators of the immune system, remains to be characterized. The hypothesis of this project is that the T lymphocytes of patients with COVID-19 have a systemic exhaustion profile (defined by low effector function associated with high expression of inhibitory receptors). In other words, the T lymphocytes of patients who develop a more severe disease phenotype have an increase in the gene / protein interaction network associated with the exhaustion mechanism, influencing the severity of the disease phenotype. Thus, this project aims to characterize the mechanisms of exhaustion of the immune response of T lymphocytes in patients infected with SARS-Cov-2, with COVID-19 light and serious. We will carry out a systemic and integrative approach, investigating the CD4 + T lymphocyte transcriptome followed by specific functional assays for validating high-throughput screening (transcriptome analysis). In addition, we will perform a meta-analysis of data previously deposited in ArrayExpress and GEO (from English, Gene Expression Omnibus) to determine the networks of gene coexpression that systemically regulate the immune response to SARS-CoV-2. This large-scale experimental approach 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. This way, it will promote a translational and multidisciplinary study that will be able to 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)