Holistic characterization of T cell exhaustion in patients with Zika

Abstract

Outbreaks of arboviruses such as Zika infections in the Americas have led to a state of international public emergency. The Zika virus (ZIKV) is transmitted by the mosquito Aedes aegypti, have co-circulated throughout the world, and trigger common clinical features. Despite the global health problems caused by this etiological agent, there is a scarce knowledge about the systemic 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 of immunological factors in the control of the development of these arboviruses. So far, few studies that have previously characterized the systemic immune response to ZIKV and DENV evaluated only antigen-presenting cells (APCs, e.g. monocytes/macrophages and dendritic cells), which are the 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 the immune system, including the anti-ZIKV immunity, remains unclear. The hypothesis of this project is that the systemic exhaustion profile of T lymphocytes, i.e. the interaction network of genes/proteins associated with mechanisms of exhaustion, has relevant relation ships with different ontogenetic categories dysregulated in patients with ZIKV infection, influencing these verity of the disease phenotype. Thus, this project aims to holistically characterize regulatory mechanisms of the T lymphocyte immune response of ZIKV infected patients in the convalescent phase. After laboratory screening, we will perform a systemic and integrated approach by performing a multiparametric phenotypic and functional analysis as well as structural 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 and DENV. In addition, we will perform a meta-analysis of transcriptome data from ZIKV infected cells/patients deposited in ArrayExpress and Gene Expression Omnibus (GEO) to determine gene 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, which might identify new immunopathological mechanisms and biomarkers for differential diagnosis, opening avenues for the development of specific therapies that will reduce morbidity and morbidity induced by arboviruses. (AU)