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Systemic and integrative analysis of T lymphocyte exhaustion mechanisms in patients with Dengue

Grant number: 20/11710-2
Support type:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): December 01, 2020
Effective date (End): November 30, 2024
Field of knowledge:Biological Sciences - Immunology
Principal Investigator:Otávio Cabral Marques
Grantee:Desirée Rodrigues Plaça
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:18/18886-9 - Systemic and integrative analysis of the immune response to Zika and Dengue viral infections, AP.JP

Abstract

Dengue outbreaks in Latin America, Africa, and Asia, transmitted by the mosquito Aedes aegypti, represents a state of international public emergency. In 2019, more than 3 million people were affected by the disease in the Americas, with about 30 million reported deaths. Despite the seriousness of this public health problem, there are no specific therapies that effectively combat Dengue and the knowledge regarding the systemic immunological mechanisms that control or develop the infection are still scarce. The fact that about 40-80% of people infected with dengue virus (DENV) are asymptomatic suggests that the immune profile (intrinsic factors) of infected individuals affects the development and evolution of DENV infections. In this context, during the acute phase of infection, T lymphocytes undergo differentiation and accompany robust proliferation. However, during chronic infections, there is a progressive loss of T lymphocyte response, a phenomenon called T lymphocyte exhaustion. Among the characteristics of exhausted T lymphocytes are positive regulation and co-expression of multiple inhibitory receptors, reduced production of cytokines, decreased proliferative capacity, and an altered epigenetic profile (for example demethylation of inhibitory receptor sites). The hypothesis of this project is that T lymphocytes of patients who develop Dengue have an altered immunoregulatory systemic profile, due to an immune predisposition to the phenomenon of exhaustion. I.e. the network of genes/proteins interaction associated with the exhaustion mechanism has relevant relationships with different ontogenetic categories deregulated in Dengue, influencing the severity phenotype of infected patients. Thus, the objective of this project is to holistically characterize new mechanisms involved in the T lymphocytes exhaustion induced by DENV, evaluating samples ate seventh and fourteenth day after the onset of symptoms, as well as 6 months after infection, through multiparametric phenotyping and cytokine array analysis. Also, we will investigate the interactome of genes and proteins involved in this process carrying out RNA sequencing (RNAseq) and mass spectrometry (MS), which will be followed by functional tests to validate the results from these two high throughput analyses. In addition, we will perform a systemic and integrative approach through a metanalysis of data previously uploaded on ArrayExpress and GEO (Gene Expression Omnibus) to determine the networks of gene co-expression that systematically regulate the immune response to DENV and its relationships with other flaviviruses (e.g. ZIKV, YFV, WNV). Thus, we will define the common and specific immunogenetic signatures, signaling pathways, and interactome involved in response to flaviviruses. The combination of a large-scale experimental approach with Computational methods for data integration will promote a translational and multidisciplinary study that might identify new biomarkers for differential diagnosis and development of specific therapies to reduce mortality and morbidity of infected patients. (AU)