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Holistic characterization of T cell exhaustion in patients with Zika

Grant number: 20/16246-2
Support type:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): January 01, 2021
Effective date (End): December 31, 2024
Field of knowledge:Biological Sciences - Immunology
Principal Investigator:Otávio Cabral Marques
Grantee:Dennyson Leandro Mathias da Fonseca
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

Outbreaks of arboviruses such as Zika infections in the Americas have led to a state ofinternational public emergency. The Zika virus (ZIKV) is transmitted by the mosquito Aedesaegypti, have co-circulated throughout the world, and trigger common clinical features. Despitethe global health problems caused by this etiological agent, there is a scarce knowledge about thesystemic immunological mechanisms that regulate the development of ZIKV infection inhumans. Consequently, no specific effective therapies to combat these diseases is available.Notably, most people infected with ZIKV are asymptomatic carriers, suggesting the influence ofimmunological factors in the control of the development of these arboviruses. So far, few studiesthat have previously characterized the systemic immune response to ZIKV and DENV evaluatedonly antigen-presenting cells (APCs, e.g. monocytes/macrophages and dendritic cells), which arethe most permissive cells and major route of dispersion of these pathogens throughout the body.However, the response of T lymphocytes, which are essential effector and regulatory cells of theimmune system, including the anti-ZIKV immunity, remains unclear. The hypothesis of thisproject is that the systemic exhaustion profile of T lymphocytes, i.e. the interaction network ofgenes/proteins associated with mechanisms of exhaustion, has relevant relationships withdifferent ontogenetic categories dysregulated in patients with ZIKV infection, influencing theseverity of the disease phenotype. Thus, this project aims to holistically characterize regulatorymechanisms of the T lymphocyte immune response of ZIKV infected patients in theconvalescent phase. After laboratory screening, we will perform a systemic and integratedapproach by performing a multiparametric phenotypic and functional analysis as well asstructural and functional transcriptome evaluation. This approach will allow us to characterizethe T cell exhaustion, immunological signatures, signaling pathways and networks of commonand specific gene-gene interactions (interactoma) involved in the immune response to ZIKV andDENV. In addition, we will perform a meta-analysis of transcriptome data from ZIKV infectedcells/patients deposited in ArrayExpress and Gene Expression Omnibus (GEO) to determinegene co-expression networks that systemically regulate the immune response to ZIKV.Therefore, this project will promote a multidisciplinary and translational study by combining alarge-scale experimental approach with a computational systemic and integrative analysis, whichmight identify new immunopathological mechanisms and biomarkers for differential diagnosis,opening avenues for the development of specific therapies that will reduce morbidity andmorbidity induced by arboviruses. (AU)