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

• Grant number: 20/11710-2
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: December 01, 2020
• End date: September 30, 2024
• Field of knowledge: Biological Sciences - Immunology
• Principal Investigator: Otávio Cabral Marques
• Grantee: Desirée Rodrigues Plaça
• Host 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
• Associated scholarship(s): 22/08116-7 - Longitudinal characterization of immunoregulatory mechanisms and host protection in dengue virus infection, BE.EP.DD

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)

Scientific publications

(6)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

FONSECA, DENNYSON LEANDRO M.; FILGUEIRAS, IGOR SALERNO; MARQUES, ALEXANDRE H. C.; VOJDANI, ELROY; HALPERT, GILAD; OSTRINSKI, YURI; BAIOCCHI, GABRIELA CRISPIM; PLACA, DESIREE RODRIGUES; FREIRE, PAULA P.; POUR, SHAHAB ZAKI; et al. Severe COVID-19 patients exhibit elevated levels of autoantibodies targeting cardiolipin and platelet glycoprotein with age: a systems biology approach. NPJ AGING, v. 9, n. 1, p. 14-pg., 2023-08-24. (20/11710-2, 20/09146-1, 20/16246-2, 20/01688-0, 20/07069-0, 20/07972-1, 18/18886-9)

PRADO, CAROLINE ALIANE DE SOUZA; FONSECA, DENNYSON LEANDRO M.; SINGH, YOUVIKA; FILGUEIRAS, IGOR SALERNO; BAIOCCHI, GABRIELA CRISPIM; PLACA, DESIREE RODRIGUES; MARQUES, ALEXANDRE H. C.; DANTAS-KOMATSU, RAQUEL COSTA SILVA; USUDA, JULIA N.; FREIRE, PAULA PACCIELLI; et al. Integrative systems immunology uncovers molecular networks of the cell cycle that stratify COVID-19 severity. Journal of Medical Virology, v. 95, n. 2, p. 18-pg., 2023-02-01. (20/11710-2, 20/09146-1, 20/16246-2, 20/01688-0, 20/07069-0, 20/07972-1, 18/18886-9)

CABRAL-MARQUES, OTAVIO; HALPERT, GILAD; SCHIMKE, LENA F.; OSTRINSKI, YURI; VOJDANI, ARISTO; BAIOCCHI, GABRIELA CRISPIM; FREIRE, PAULA PACCIELLI; FILGUEIRAS, IGOR SALERNO; ZYSKIND, ISRAEL; LATTIN, MIRIAM T.; et al. Autoantibodies targeting GPCRs and RAS-related molecules associate with COVID-19 severity. NATURE COMMUNICATIONS, v. 13, n. 1, p. 12-pg., 2022-03-09. (20/07069-0, 18/18886-9, 20/16246-2, 20/11710-2, 20/07972-1, 20/09146-1, 20/01688-0)

SOTZNY, FRANZISKA; FILGUEIRAS, IGOR SALERNO; KEDOR, CLAUDIA; FREITAG, HELMA; WITTKE, KIRSTEN; BAUER, SANDRA; SEPULVEDA, NUNO; MATHIAS DA FONSECA, DENNYSON LEANDRO; BAIOCCHI, GABRIELA CRISPIM; MARQUES, ALEXANDRE H. C.; et al. Dysregulated autoantibodies targeting vaso- and immunoregulatory receptors in Post COVID Syndrome correlate with symptom severity. FRONTIERS IN IMMUNOLOGY, v. 13, p. 17-pg., 2022-09-27. (20/16246-2, 20/01688-0, 20/07069-0, 18/18886-9, 20/11710-2, 20/07972-1)

USUDA, JULIA NAKANISHI; PLACA, DESIREE RODRIGUES; FONSECA, DENNYSON LEANDRO M.; MARQUES, ALEXANDRE H. C.; FILGUEIRAS, IGOR SALERNO; CHAVES, VICTOR GABRIEL BASTOS; ADRI, ANNY SILVA; TORRENTES-CARVALHO, AMANDA; HIRATA, MARIO HIROYUKI; FREIRE, PAULA PACCIELLI; et al. Interferome signature dynamics during the anti-dengue immune response: a systems biology characterization. FRONTIERS IN IMMUNOLOGY, v. 14, p. 16-pg., 2023-08-10. (20/16246-2, 20/11710-2, 23/03841-8, 18/18886-9, 21/03675-5)

PLACA, DESIREE RODRIGUES; FONSECA, DENNYSON LEANDRO M.; MARQUES, ALEXANDRE H. C.; ZAKI POUR, SHAHAB; USUDA, JULIA NAKANISHI; BAIOCCHI, GABRIELA CRISPIM; PRADO, CAROLINE ALIANE DE SOUZA; SALGADO, RANIERI COELHO; FILGUEIRAS, IGOR SALERNO; FREIRE, PAULA PACCIELLI; et al. Immunological signatures unveiled by integrative systems vaccinology characterization of dengue vaccination trials and natural infection. FRONTIERS IN IMMUNOLOGY, v. 15, p. 17-pg., 2024-02-20. (20/16246-2, 20/07069-0, 20/09146-1, 20/01688-0, 18/18886-9, 20/07972-1, 20/11710-2, 21/03675-5)