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

• Grant number: 18/18886-9
• Support Opportunities: Research Grants - Young Investigators Grants
• Start date: February 01, 2020
• End date: January 31, 2026
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: Otávio Cabral Marques
• Grantee: Otávio Cabral Marques
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated researchers: Antonio Condino Neto ; Jean Pierre Schatzmann Peron ; Niels Olsen Saraiva Câmara ; Paolo Marinho de Andrade Zanotto ; Vera Lucia Garcia Calich
• Associated research grant(s): 20/07069-0 - Systemic and integrative analysis of T lymphocyte exhaustion mechanisms in patients with COVID-19, AP.R
• Associated scholarship(s): 23/12268-0 - Integrative systemic characterization of the neuroimmunological interactions of Major Depressive Disorder and its intersection with post-COVID-19 syndrome, BP.MS; 23/07806-2 - Integrative systems bioinformatics analysis of antiviral immune responses., BP.TT; 23/06086-6 - SYSTEMIC INTEGRATIVE ANALYSIS OF TUMORS ASSOCIATED WITH HUMAN ONCOVIRUS INFECTIONS, BP.MS; + associated scholarships 23/03841-8 - Holistic and functional investigation of the neuroimmune interactions networks during the pathophysiology of neuroinvasive viral infections, BP.MS; 21/03675-5 - Analysis of the network of IFN-associated molecules in Dengue fever patients, BP.IC; 20/16246-2 - Holistic characterization of T cell exhaustion in patients with Zika, BP.DD; 20/11710-2 - Systemic and integrative analysis of T lymphocyte exhaustion mechanisms in patients with Dengue, BP.DD; 20/07972-1 - Systemic and integrative analysis of T lymphocyte exhaustion mechanisms in patients with COVID-19, BP.DD; 20/02237-1 - Systemic and integrative analysis of the immune response to Zika and Dengue viral infections, BP.IC; 20/01688-0 - Systemic and integrative analysis of the immune response to Zika and Dengue viral infections, BP.JP - associated scholarships

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 a 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, 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)

Scientific publications

(24)

(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)

FRANCA, TABATA TAKAHASHI; AL-SBIEI, ASHRAF; BASHIR, GHADA; MOHAMED, YASSIR AWAD; SALGADO, RANIERI COELHO; BARREIROS, LUCILA AKUNE; DA SILVA NAPOLEAO, SARAH MARIA; WEBER, CRISTINA WORM; SEVERO FERREIRA, JANAIRA FERNANDES; ARANDA, CAROLINA SANCHEZ; et al. CD40L modulates transcriptional signatures of neutrophils in the bone marrow associated with development and trafficking. JCI INSIGHT, v. 6, n. 16, AUG 23 2021. (16/22158-3, 20/01688-0, 18/18886-9, 17/04187-9, 20/07069-0)

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)

MOHAMED, KAWTHAR; RZYMSKI, PIOTR; ISLAM, MD SHAHIDUL; MAKUKU, RANGARIRAI; MUSHTAQ, AYESHA; KHAN, AMJAD; IVANOVSKA, MARIYA; MAKKA, SARA A.; HASHEM, FAREEDA; MARQUEZ, LEANDER; et al. OVID-19 vaccinations: The unknowns, challenges, and hope. Journal of Medical Virology, v. 94, n. 4, DEC 2021. (20/07069-0, 18/18886-9, 20/01688-0)

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)

BORGES, LYSANDRO P.; GUIMARAES, ADRIANA G.; FONSECA, DENNYSON LEANDRO M.; FREIRE, PAULA P.; BARRETO, IKARO D. C.; SOUZA, DANIELA R., V; GURGEL, RICARDO Q.; LOPES, ALINE S. A.; DE REZENDE NETO, JOSE MELQUIADES; DOS SANTOS, KEZIA A.; et al. Cross-sectional analysis of students and school workers reveals a high number of asymptomatic SARS-CoV-2 infections during school reopening in Brazilian cities. HELIYON, v. 8, n. 11, p. 11-pg., 2022-11-07. (20/01688-0, 18/18886-9, 20/09146-1, 20/07069-0)

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)

GUIMARAES, GABRIELA RAPOZO; MAKLOUF, GIOVANNA RESK; TEIXEIRA, CRISTIANE ESTEVES; SANTOS, LEANDRO DE OLIVEIRA; TESSAROLLO, NAYARA GUSMAO; DE TOLEDO, NAYARA EVELIN; SERAIN, ALESSANDRA FREITAS; DE LANNA, CRISTOVAO ANTUNES; PRETTI, MARCO ANTONIO; DA CRUZ, JESSICA GONCALVES VIEIRA; et al. Single-cell resolution characterization of myeloid-derived cell states with implication in cancer outcome. NATURE COMMUNICATIONS, v. 15, n. 1, p. 23-pg., 2024-07-07. (18/18886-9, 20/07069-0, 20/01688-0, 23/07806-2)

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)

MOLL, GUIDO; LUECHT, CHRISTIAN; GYAMFI, MICHAEL ADU; DA FONSECA, DENNYSON L. M.; WANG, PINCHAO; ZHAO, HONGFAN; GONG, ZEXIAN; CHEN, LEI; ASHRAF, MUHAMAD IMTIAZ; HEIDECKE, HARALD; et al. Autoantibodies from patients with kidney allograft vasculopathy stimulate a proinflammatory switch in endothelial cells and monocytes mediated via GPCR-directed PAR1-TNF-α signaling. FRONTIERS IN IMMUNOLOGY, v. 14, p. 15-pg., 2023-10-30. (18/18886-9, 20/07069-0, 20/01688-0)

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)

FRANCA, TABATA TAKAHASHI; BARREIROS, LUCILA AKUNE; SALGADO, RANIERI COELHO; DA SILVA NAPOLEAO, SARAH MARIA; GOMES, LILLIAN NUNES; SEVERO FERREIRA, JANAIRA FERNANDES; PRANDO, CAROLINA; WEBER, CRISTINA WORM; WATANABE DI GESU, REGINA SUMIKO; MONTENEGRO, CECILIA; et al. CD40 Ligand Deficiency in Latin America: Clinical, Immunological, and Genetic Characteristics. JOURNAL OF CLINICAL IMMUNOLOGY, JAN 2022. (20/01688-0, 17/04187-9, 18/18886-9, 16/22158-3)

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)

DANTAS-KOMATSU, RAQUEL COSTA SILVA; CRUZ, MARINA SAMPAIO; FREIRE, PAULA PACCIELLI; DINIZ, ROSIANE VIANA ZUZA; BORTOLIN, RAUL HERNANDES; CABRAL-MARQUES, OTAVIO; SOUZA, KAMILLA BATISTA DA SILVA; HIRATA, MARIO HIROYUKI; HIRATA, ROSARIO DOMINGUEZ CRESPO; REIS, BRUNA ZAVARIZE; et al. The let-7b-5p, miR-326, and miR-125a-3p are associated with left ventricular systolic dysfunction in post-myocardial infarction. FRONTIERS IN CARDIOVASCULAR MEDICINE, v. 10, p. 11-pg., 2023-05-12. (20/09146-1, 18/18886-9, 20/01688-0, 20/07069-0)

FILGUEIRAS, IGOR SALERNO; TORRENTES DE CARVALHO, AMANDA; CUNHA, DANIELA PRADO; MATHIAS DA FONSECA, DENNYSON LEANDRO; EL KHAWANKY, NADIA; FREIRE, PAULA PACCIELLI; CABRAL-MIRANDA, GUSTAVO; SCHIMKE, LENA F.; CAMARA, NIELS OLSEN SARAIVA; OCHS, HANS D.; et al. The clinical spectrum and immunopathological mechanisms underlying ZIKV-induced neurological manifestations. PLoS Neglected Tropical Diseases, v. 15, n. 8, AUG 2021. (18/18886-9, 20/09146-1, 17/05264-7, 20/01688-0)

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)

SALGADO, RANIERI COELHO; FONSECA, DENNYSON LEANDRO M.; MARQUES, ALEXANDRE H. C.; DA SILVA NAPOLEAO, SARAH MARIA; FRANCA, TABATA TAKAHASHI; AKASHI, KAREN TIEMI; DE SOUZA PRADO, CAROLINE ALIANE; BAIOCCHI, GABRIELA CRISPIM; PLACA, DESIREE RODRIGUES; JANSEN-MARQUES, GABRIEL; et al. The network interplay of interferon and Toll-like receptor signaling pathways in the anti-Candida immune response. SCIENTIFIC REPORTS, v. 11, n. 1, OCT 13 2021. (20/01688-0, 18/18886-9, 20/07069-0)

BORGES, LYSANDRO PINTO; DE JESUS, PAMELA CHAVES; DE SOUZA, JESSIANE BISPO; SILVA, DEISE MARIA REGO RODRIGUES; MOURA, PEDRO HENRIQUE MACEDO; SANTOS, RONALDY SANTANA; BARRETO, MARINA DOS SANTOS; GUIMARAES, ADRIANA GIBARA; SANTANA, LUCAS ALVES DA MOTA; DA FONSECA, DENNYSON LEANDRO MATHIAS; et al. The Impact of Diabetes Education on Continuous Glucose Monitoring in SUS-Dependent Patients in a Northeastern Brazilian City. LIFE-BASEL, v. 14, n. 3, p. 14-pg., 2024-03-01. (18/18886-9, 23/13356-0)

ASGHAR, MUHAMMAD; KHAN, TAJ ALI; SERAPHIN, MARIE NANCY; SCHIMKE, LENA F.; CABRAL-MARQUES, OTAVIO; HAQ, IHTISHAM UL; FAROOQI, ZIA-UR-REHMAN; CAMPINO, SUSANA; ULLAH, IHSAN; CLARK, TAANE G.. Exploring the Antimicrobial Resistance Profile of Salmonella typhi and Its Clinical Burden. ANTIBIOTICS-BASEL, v. 13, n. 8, p. 12-pg., 2024-08-01. (18/18886-9)

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)

WANG, PINCHAO; WU, DASHAN; GONG, ZEXIAN; ADU-GYAMFI, MICHAEL; KAMHIEH-MILZ, JULIAN; DA FONSECA, DENNYSON LEANDRO MATHIAS; SUERUECUE, GUELISTAN; ASHRAF, MUHAMMAD I.; HEIDECKE, HARALD; SIKORSKA, DOROTA; et al. Stimulation of endothelin-1 production by autoantibodies present in patients with scleroderma renal crisis. Clinical Immunology, v. 273, p. 10-pg., 2025-02-20. (20/07069-0, 20/01688-0, 18/18886-9)

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)