Holistic characterization of T cell exhaustion in patients with Zika

• Grant number: 20/16246-2
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: January 01, 2021
• End date: March 31, 2025
• Field of knowledge: Biological Sciences - Immunology
• Principal Investigator: Otávio Cabral Marques
• Grantee: Dennyson Leandro Mathias da Fonseca
• 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): 23/13356-0 - The analysis of neutrophil-activating autoantibodies: a thrombosis perspective, BE.EP.DD

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)

Scientific publications

(12)

(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; MOLL, GUIDO; CATAR, RUSAN; PREUSS, BEATE; BANKAMP, LUKAS; PECHER, ANN-CHRISTIN; HENES, JOERG; KLEIN, REINHILD; KAMALANATHAN, A. S.; AKBARZADEH, REZA; et al. Autoantibodies targeting G protein-coupled receptors: An evolving history in autoimmunity. Report of the 4th international symposium. AUTOIMMUNITY REVIEWS, v. 22, n. 5, p. 14-pg., 2023-03-14. (18/18886-9, 20/16246-2, 20/01688-0, 20/07069-0, 20/07972-1, 20/05146-7, 19/14526-0)

BASTOS, VICTOR; PACHECO, VINICIUS; RODRIGUES, ERIKA D. L.; MORAES, CASSIA N. S.; NOBILE, ADRIEL L.; FONSECA, DENNYSON LEANDRO M.; SOUZA, KAMILLA B. S.; DO VALE, FERNANDO Y. N.; FILGUEIRAS, IGOR S.; SCHIMKE, LENA F.; et al. Neuroimmunology of rabies: New insights into an ancient disease. Journal of Medical Virology, v. 95, n. 10, p. 17-pg., 2023-10-01. (23/07806-2, 18/18886-9, 20/16246-2)

BARRETO, MARINA DOS SANTOS; DA SILVA, BEATRIZ SOARES; SANTOS, RONALDY SANTANA; SILVA, DEISE MARIA REGO RODRIGUES; SILVA, ELOIA EMANUELLY DIAS; MOURA, PEDRO HENRIQUE MACEDO; DE SOUZA, JESSIANE BISPO; SANTANA, LUCAS ALVES DA MOTA; FONSECA, DENNYSON LEANDRO M.; FILGUEIRAS, IGOR SALERNO; et al. COVID-19 Vaccination and Serological Profile of a Brazilian University Population. LIFE-BASEL, v. 13, n. 9, p. 14-pg., 2023-09-01. (18/18886-9, 20/16246-2, 23/07806-2)

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)

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)

COUTO, PEDRO S.; AL-ARAWE, NADA; FILGUEIRAS, IGOR S.; FONSECA, DENNYSON L. M.; HINTERSEHER, IRENE; CATAR, RUSAN A.; CHINNADURAI, RAGHAVAN; BERSENEV, ALEXEY; CABRAL-MARQUES, OTAVIO; MOLL, GUIDO; et al. Systematic review and meta-analysis of cell therapy for COVID-19: global clinical trial landscape, published safety/efficacy outcomes, cell product manufacturing and clinical delivery. FRONTIERS IN IMMUNOLOGY, v. 14, p. 24-pg., 2023-06-21. (18/18886-9, 20/16246-2, 20/01688-0, 20/07069-0)

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)

FONSECA, DENNYSON LEANDRO M.; JAEPEL, MAJ; GYAMFI, MICHAEL ADU; FILGUEIRAS, IGOR SALERNO; BAIOCHI, GABRIELA CRISPIM; OSTRINSKI, YURI; HALPERT, GILAD; LAVI, YAEL BUBLIL; VOJDANI, ELROY; SILVA-SOUSA, THAYNA; et al. Dysregulated autoantibodies targeting AGTR1 are associated with the accumulation of COVID-19 symptoms. NPJ SYSTEMS BIOLOGY AND APPLICATIONS, v. 11, n. 1, p. 13-pg., 2025-01-13. (20/16246-2, 19/27139-5, 18/18886-9, 20/01688-0, 23/13356-0, 20/07972-1, 23/12268-0, 23/07806-2, 23/06086-6, 20/09146-1, 20/07069-0)

SILVA-SOUSA, THAYNA; USUDA, JULIA NAKANISHI; AL-ARAWE, NADA; FRIAS, FRANCISCA; HINTERSEHER, IRENE; CATAR, RUSAN; LUECHT, CHRISTIAN; RIESNER, KATARINA; HACKEL, ALEXANDER; SCHIMKE, LENA F.; et al. The global evolution and impact of systems biology and artificial intelligence in stem cell research and therapeutics development: a scoping review. Stem Cells, v. 42, n. 11, p. 16-pg., 2024-10-13. (20/16246-2, 20/07069-0, 23/07806-2, 20/01688-0, 18/18886-9)

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)