Systemic and integrative analysis of the immune response to Zika and Dengue viral infections

Abstract

Outbreaks of arboviruses such as Zika e Dengue in the Americas have led to a state of international public emergency. The viruses are transmitted by the same vector mosquito (Aedes aegypti), have co-circulated throughout the world, and trigger common clinical features. Despite the global health problems caused by these etiological agents, there is scarce knowledge about the systemic immunological mechanisms that regulate the development of the infections caused by the two viruses (ZIKV and DENV). Consequently, no specific effective therapies to combat these diseases is available. Notably, most people infected with ZIKV and DENV 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, eg 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 CD4+ and CD8+ T lymphocytes, which are essential effector and regulatory cells of ZIKV and DENV immunity, remains unclear. This project aims to identify regulatory mechanisms of the T lymphocyte immune response of patients in the convalescent phase of infection. 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 characterize the T cell exhaustion, immunological signatures, signaling pathways and networks of common and specific gene-gene interactions (interactoma) involved in the immune response to ZIKV and DENV. In addition, we will perform a meta-analysis of APC transcriptome data previously submitted to ArrayExpress and Gene Expression Omnibus (GEO) to determine gene co-expression networks that systemically regulate the immune response to ZIKV and DENV and construct a database of the immune response to these two arboviruses. Furthermore, metanalysis of transcriptomic data of APCs previously deposited in the databases ArrayExpress and Gene Expression Omnibus (GEO) will be performed to determine the gene go-expression networks that regulate the immune response to ZIKV and DENV. Therefore, it will promote a multidisciplinary and translational study by combining a large-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)